University of Liverpool
Neutrophils and redox stress in the pathogenesis of autoimmune diseaseLaurence Glennon-Alty*1,2, Angela P Hackett*1, Elinor A Chapman*1, Helen L Wright11Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK2Liverpool Health Partners, University of Liverpool, Liverpool, UK*contributed equallyCorresponding Author:Dr Helen L Wright, Department of Musculoskeletal Biology, Institute of Ageing and Chronic Disease, University of Liverpool, 6 West Derby Street, Liverpool, UK L7 8TXTel: 0151 795 4457Email: hlwright@liverpool.ac.ukAbstractPolymorphonuclear leukocytes, or neutrophils, are specialist phagocytic cells of the innate immune system. Their primary role is host defence against micro-organisms, which they kill via phagocytosis, followed by release of reactive oxygen species (ROS) and proteolytic enzymes within the phagosome. ROS are generated via the action of the NADPH oxidase (also known as NOX2), in a process termed the ‘Respiratory Burst’. This process consumes large amounts of oxygen, which is converted into the highly-reactive superoxide radical O2- and H2O2. Subsequent activation of myeloperoxidase (MPO) generates secondary oxidants and chloroamines that are highly microbiocidal in nature, which together with proteases such as elastase and gelatinase provide a toxic intra-phagosomal environment able to kill a broad range of micro-organisms. However, under certain circumstances such as during an auto-immune response, neutrophils can be triggered to release ROS and proteases extracellularly causing damage to host tissues, modification of host proteins, lipids and DNA and dysregulation of oxidative homeostasis. This review describes the range of ROS species produced by human neutrophils with a focus on the implications of neutrophil redox products in autoimmune inflammation.KeywordsNeutrophil, ROS, Redox, Auto-immune, Rheumatoid arthritis, Systemic Lupus Erythematosus, Vasculitis, Beh?ets disease, Psoriasis, Multiple SclerosisAbbreviationsANCAAnti-neutrophil cytoplasmic antibodyAPSAnti-phospholipid syndromeERKExtracellular signal–regulated kinaseFcγRFcγ ReceptorFMLPf-Met-Leu-PheGM-CSFGranulocyte/macrophage-colony stimulating factorIgGImmunoglobulin GMAPKMitogen-activated protein kinaseMPOMyeloperoxidasemtROSMitochondrial ROSNADPNicotinamide adenine dinucleotide phosphateNADPHNicotinamide adenine dinucleotide phosphate, reduced formNETNeutrophil extracellular trapNF-κBNuclear factor kappa-light-chain-enhancer of activated B cellsNOXNADPH oxidaseNrf2Nuclear factor erythroid 2-related factorPhoxPhagocyte oxidasePMAPhorbol?12-myristate 13-acetatePR3Proteinase 3RARheumatoid arthritisSLESystemic lupus erythematosusTNFTumour necrosis factorVEGFVascular endothelial growth factorIntroductionNeutrophils are specialist cells of the innate immune system that play a major role in host defence through phagocytosis and generation of reactive oxygen species (ROS). Production of ROS within the phagosome occurs via the action of NADPH oxidase (NOX2) and myeloperoxidase (MPO), and together with release of proteases from intracellular vesicles into the phagosome, provides a defensive arsenal against a broad spectrum of microscopic pathogens. During infection, ROS and proteases may be released extracellularly causing local tissue damage at the site of infection ADDIN EN.CITE <EndNote><Cite><Author>Wright</Author><Year>2010</Year><RecNum>279</RecNum><DisplayText>[1]</DisplayText><record><rec-number>279</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1519647528">279</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wright, H. L.</author><author>Moots, R. J.</author><author>Bucknall, R. C.</author><author>Edwards, S. W.</author></authors></contributors><auth-address>School of Biological Sciences, University of Liverpool, UK.</auth-address><titles><title>Neutrophil function in inflammation and inflammatory diseases</title><secondary-title>Rheumatology (Oxford)</secondary-title></titles><periodical><full-title>Rheumatology (Oxford)</full-title><abbr-1>Rheumatology</abbr-1></periodical><pages>1618-31</pages><volume>49</volume><number>9</number><edition>2010/03/27</edition><keywords><keyword>Antirheumatic Agents/*therapeutic use</keyword><keyword>Apoptosis/physiology</keyword><keyword>Arthritis, Rheumatoid/drug therapy/*metabolism/physiopathology</keyword><keyword>Cytokines/drug effects/*metabolism/physiology</keyword><keyword>Humans</keyword><keyword>Inflammation/*metabolism/physiopathology</keyword><keyword>Neutrophils/drug effects/*metabolism/physiology</keyword></keywords><dates><year>2010</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1462-0332 (Electronic)
1462-0324 (Linking)</isbn><accession-num>20338884</accession-num><urls><related-urls><url> [pii]
10.1093/rheumatology/keq045</electronic-resource-num><language>eng</language></record></Cite></EndNote>[1]. This damage is normally resolved by resident macrophages, which phagocytose apoptotic neutrophils and damaged tissue as part of the normal process of inflammation resolution ADDIN EN.CITE <EndNote><Cite><Author>Koh</Author><Year>2011</Year><RecNum>278</RecNum><DisplayText>[2]</DisplayText><record><rec-number>278</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1519647450">278</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Koh, T. J.</author><author>DiPietro, L. A.</author></authors></contributors><auth-address>Department of Kinesiology & Nutrition, College of Applied Health Sciences, Center for Wound Healing and Tissue Regeneration, Chicago, IL, USA.</auth-address><titles><title>Inflammation and wound healing: the role of the macrophage</title><secondary-title>Expert Rev Mol Med</secondary-title><alt-title>Expert reviews in molecular medicine</alt-title></titles><periodical><full-title>Expert Rev Mol Med</full-title><abbr-1>Expert reviews in molecular medicine</abbr-1></periodical><alt-periodical><full-title>Expert Rev Mol Med</full-title><abbr-1>Expert reviews in molecular medicine</abbr-1></alt-periodical><pages>e23</pages><volume>13</volume><edition>2011/07/12</edition><keywords><keyword>Apoptosis</keyword><keyword>Cell Proliferation</keyword><keyword>Fibrosis</keyword><keyword>Humans</keyword><keyword>Hypoxia</keyword><keyword>*Inflammation</keyword><keyword>Intercellular Signaling Peptides and Proteins/biosynthesis</keyword><keyword>Leukocytes</keyword><keyword>Macrophages/*physiology</keyword><keyword>Neovascularization, Physiologic</keyword><keyword>*Wound Healing</keyword></keywords><dates><year>2011</year><pub-dates><date>Jul 11</date></pub-dates></dates><isbn>1462-3994 (Electronic)
1462-3994 (Linking)</isbn><accession-num>21740602</accession-num><work-type>Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Review</work-type><urls><related-urls><url>;[2]. Neutrophils also contribute to inflammation and tissue damage in inflammatory disease, whereby they become inappropriately activated by cytokines, chemokines and auto-antibodies ADDIN EN.CITE <EndNote><Cite><Author>Wright</Author><Year>2010</Year><RecNum>279</RecNum><DisplayText>[1]</DisplayText><record><rec-number>279</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1519647528">279</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wright, H. L.</author><author>Moots, R. J.</author><author>Bucknall, R. C.</author><author>Edwards, S. W.</author></authors></contributors><auth-address>School of Biological Sciences, University of Liverpool, UK.</auth-address><titles><title>Neutrophil function in inflammation and inflammatory diseases</title><secondary-title>Rheumatology (Oxford)</secondary-title></titles><periodical><full-title>Rheumatology (Oxford)</full-title><abbr-1>Rheumatology</abbr-1></periodical><pages>1618-31</pages><volume>49</volume><number>9</number><edition>2010/03/27</edition><keywords><keyword>Antirheumatic Agents/*therapeutic use</keyword><keyword>Apoptosis/physiology</keyword><keyword>Arthritis, Rheumatoid/drug therapy/*metabolism/physiopathology</keyword><keyword>Cytokines/drug effects/*metabolism/physiology</keyword><keyword>Humans</keyword><keyword>Inflammation/*metabolism/physiopathology</keyword><keyword>Neutrophils/drug effects/*metabolism/physiology</keyword></keywords><dates><year>2010</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1462-0332 (Electronic)
1462-0324 (Linking)</isbn><accession-num>20338884</accession-num><urls><related-urls><url> [pii]
10.1093/rheumatology/keq045</electronic-resource-num><language>eng</language></record></Cite></EndNote>[1]. Auto-immune neutrophils function in a multitude of ways to direct the inflammatory response, including release of proteases which damage host tissue and activate soluble proteins ADDIN EN.CITE <EndNote><Cite><Author>Pham</Author><Year>2006</Year><RecNum>283</RecNum><DisplayText>[3]</DisplayText><record><rec-number>283</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1521630998">283</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pham, C. T.</author></authors></contributors><auth-address>Division of Rheumatology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri 63110, USA. CPHAM@im.wustl.edu</auth-address><titles><title>Neutrophil serine proteases: specific regulators of inflammation</title><secondary-title>Nat Rev Immunol</secondary-title></titles><periodical><full-title>Nat Rev Immunol</full-title><abbr-1>Nature reviews. Immunology</abbr-1></periodical><pages>541-50</pages><volume>6</volume><number>7</number><edition>2006/06/27</edition><keywords><keyword>Animals</keyword><keyword>Humans</keyword><keyword>Infection/immunology</keyword><keyword>Inflammation/*enzymology/immunology/microbiology</keyword><keyword>Mice</keyword><keyword>*Models, Immunological</keyword><keyword>Neutrophils/*enzymology</keyword><keyword>Serine Endopeptidases/*immunology</keyword></keywords><dates><year>2006</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1474-1733 (Print)</isbn><accession-num>16799473</accession-num><urls><related-urls><url> [pii]
10.1038/nri1841</electronic-resource-num><language>eng</language></record></Cite></EndNote>[3], secretion of cytokines and chemokines which direct both the innate and adaptive immune responses ADDIN EN.CITE <EndNote><Cite><Author>Mantovani</Author><Year>2011</Year><RecNum>284</RecNum><DisplayText>[4]</DisplayText><record><rec-number>284</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1521631661">284</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mantovani, A.</author><author>Cassatella, M. A.</author><author>Costantini, C.</author><author>Jaillon, S.</author></authors></contributors><auth-address>Istituto Clinico Humanitas IRCCS, via Manzoni 56, 20089 Rozzano, Italy. alberto.mantovani@humanitasresearch.it</auth-address><titles><title>Neutrophils in the activation and regulation of innate and adaptive immunity</title><secondary-title>Nat Rev Immunol</secondary-title><alt-title>Nature reviews. Immunology</alt-title></titles><periodical><full-title>Nat Rev Immunol</full-title><abbr-1>Nature reviews. Immunology</abbr-1></periodical><alt-periodical><full-title>Nat Rev Immunol</full-title><abbr-1>Nature reviews. Immunology</abbr-1></alt-periodical><pages>519-31</pages><volume>11</volume><number>8</number><edition>2011/07/26</edition><keywords><keyword>Adaptive Immunity/*immunology</keyword><keyword>Animals</keyword><keyword>Disease/etiology</keyword><keyword>Humans</keyword><keyword>Immunity, Innate/*immunology</keyword><keyword>Neutrophils/cytology/*immunology</keyword></keywords><dates><year>2011</year><pub-dates><date>Jul 25</date></pub-dates></dates><isbn>1474-1741 (Electronic)
1474-1733 (Linking)</isbn><accession-num>21785456</accession-num><work-type>Research Support, Non-U.S. Gov't
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ADDIN EN.CITE.DATA [5,6], release of neutrophil extracellular traps (NETs) providing a source of auto-antigens ADDIN EN.CITE <EndNote><Cite><Author>Kaplan</Author><Year>2011</Year><RecNum>212</RecNum><DisplayText>[7]</DisplayText><record><rec-number>212</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511342257">212</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kaplan, M. J.</author></authors></contributors><auth-address>Division of Rheumatology, Department of Internal Medicine, University of Michigan Medical School, 1150 W Medical Center Drive, Ann Arbor, MI 48109, USA. makaplan@umich.edu.</auth-address><titles><title>Neutrophils in the pathogenesis and manifestations of SLE</title><secondary-title>Nat Rev Rheumatol</secondary-title></titles><periodical><full-title>Nat Rev Rheumatol</full-title></periodical><pages>691-9</pages><volume>7</volume><number>12</number><keywords><keyword>Animals</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/complications/*immunology/pathology</keyword><keyword>Neutropenia/complications</keyword><keyword>Neutrophils/*pathology/physiology</keyword></keywords><dates><year>2011</year><pub-dates><date>Sep 27</date></pub-dates></dates><isbn>1759-4804 (Electronic)
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ADDIN EN.CITE.DATA [8,9]. This review will provide an overview of the production of ROS by neutrophils via NOX2 and MPO, the importance of ROS for normal neutrophil functions during infection, and then present the evidence for neutrophil-derived ROS in the pathogenesis of auto-immune disease. Specifically, we will review the contribution of neutrophil-derived ROS in the pathogenesis of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), anti-phospholipid syndrome (APS), psoriasis, vasculitis and multiple sclerosis. Redox reactions in neutrophilsNADPH Oxidase (NOX) derived oxidants Neutrophils are innate immune cells which primarily function in host defence through phagocytosis of micro-organisms and release of ROS via the ‘Respiratory Burst’. The production of ROS within the neutrophil phagosome, in concert with the secretion of granule proteases, provides a broad-spectrum cytotoxic environment sufficient to kill a wide range of bacterial and fungal pathogens. The primary source of immune-active ROS in neutrophils is the NADPH oxidase (NOX2). NOX2 is a multi-component enzyme, which is assembled at the phagosomal and plasma membranes of neutrophils upon receipt of a “priming” signal, e.g. activation of a cytokine receptorPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYW5nPC9BdXRob3I+PFllYXI+MTk5OTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [13,14]. Assembly of NOX2 at the plasma membrane leads to the release of oxygen radicals into the extracellular environment, and is a major cause of redox stress in auto-immune disease.The cytosolic phox components of the oxidase are inactive in the cytosol of resting neutrophils. However, upon priming by agents such as lipopolysaccharide, TNF and GM-CSF, the phox proteins are rapidly phosphorylated by protein tyrosine kinases (including p38 MAPK, ERK, and protein kinase CPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYW5nPC9BdXRob3I+PFllYXI+MTk5OTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [10,15,16]), and mobilised to the plasma membrane where they complex with cytochrome b558 (Figure 1)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYW5nPC9BdXRob3I+PFllYXI+MjAwMTwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [17]. Phosphorylated p40phox and p47phox act as adaptor proteins, enabling binding of p67phox to cytochrome b558PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYW5nPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [19-21]. Simultaneous binding of all cytosolic components to cytochrome b558 is essential for the formation of an efficient catalytic enzyme complex ADDIN EN.CITE <EndNote><Cite><Author>Karimi</Author><Year>2014</Year><RecNum>21</RecNum><DisplayText>[22]</DisplayText><record><rec-number>21</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1507554455">21</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Karimi, G.</author><author>Houee Levin, C.</author><author>Dagher, M. C.</author><author>Baciou, L.</author><author>Bizouarn, T.</author></authors></contributors><auth-address>Laboratoire de Chimie Physique, Universite Paris Sud, UMR8000, CNRS, Orsay F-91405, France.
Laboratoire TIMC-IMAG, Equipe TheREx, UMR5525, 38710 La Tronche, France.
Laboratoire de Chimie Physique, Universite Paris Sud, UMR8000, CNRS, Orsay F-91405, France; Laboratoire de Chimie Physique, bat 350, Universite Paris Sud, 91405 Orsay cedex, France. Electronic address: ouarn@u-psud.fr.</auth-address><titles><title>Assembly of phagocyte NADPH oxidase: A concerted binding process?</title><secondary-title>Biochim Biophys Acta</secondary-title><alt-title>Biochimica et biophysica acta</alt-title></titles><periodical><full-title>Biochim Biophys Acta</full-title><abbr-1>Biochimica et biophysica acta</abbr-1></periodical><alt-periodical><full-title>Biochim Biophys Acta</full-title><abbr-1>Biochimica et biophysica acta</abbr-1></alt-periodical><pages>3277-83</pages><volume>1840</volume><number>11</number><edition>2014/08/12</edition><keywords><keyword>Arachidonic acid activation</keyword><keyword>Cell free system</keyword><keyword>NADPH oxidase (Nox)</keyword><keyword>Neutrophil</keyword><keyword>Protein translocation</keyword></keywords><dates><year>2014</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0006-3002 (Print)
0006-3002 (Linking)</isbn><accession-num>25108064</accession-num><urls><related-urls><url>;[22]. A number of proteins, such as phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and S100A8/A9, have been identified as enhancing NOX2 activity at the phagosomal membrane either by controlling the rate of mobilisation of phox components or enhancing electron transferase activation ADDIN EN.CITE <EndNote><Cite><Author>Nunes</Author><Year>2013</Year><RecNum>23</RecNum><DisplayText>[23]</DisplayText><record><rec-number>23</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1507554455">23</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Nunes, P.</author><author>Demaurex, N.</author><author>Dinauer, M. C.</author></authors></contributors><auth-address>Department of Cell Physiology and Metabolism, University of Geneva, 1 rue Michel-Servet, CH-1211, Geneva 4, Switzerland.</auth-address><titles><title>Regulation of the NADPH oxidase and associated ion fluxes during phagocytosis</title><secondary-title>Traffic</secondary-title><alt-title>Traffic</alt-title></titles><periodical><full-title>Traffic</full-title><abbr-1>Traffic</abbr-1></periodical><alt-periodical><full-title>Traffic</full-title><abbr-1>Traffic</abbr-1></alt-periodical><pages>1118-31</pages><volume>14</volume><number>11</number><edition>2013/08/29</edition><keywords><keyword>Animals</keyword><keyword>Humans</keyword><keyword>Ion Transport</keyword><keyword>NADPH Oxidase/*metabolism</keyword><keyword>*Phagocytosis</keyword><keyword>Phagosomes/*metabolism</keyword><keyword>Protein Transport</keyword><keyword>Reactive Oxygen Species/metabolism</keyword><keyword>Hv1</keyword><keyword>Nox2</keyword><keyword>Stim1</keyword><keyword>dendritic cell</keyword><keyword>granulocyte</keyword><keyword>macrophage</keyword><keyword>neutrophil</keyword><keyword>p47phox</keyword><keyword>p67phox</keyword><keyword>superoxide</keyword></keywords><dates><year>2013</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1600-0854 (Electronic)
1398-9219 (Linking)</isbn><accession-num>23980663</accession-num><work-type>Research Support, Non-U.S. Gov't
Review</work-type><urls><related-urls><url>;[23].Activation of the respiratory burst normally requires a second signal following priming of the cell and assembly of NOX2. This is usually the activation of Fcγ and/or complement receptors following phagocytosis of opsonised pathogens, or activation of the f-Met-Leu-Phe (fMLP) receptor. Upon activation, assembled NOX2 catalyses the reduction of O2 to the superoxide radical O2- in the reaction NADPH + 2O2 → 2O2- + H+ + NADP+ (Figure 1). The superoxide radical is unstable, and rapidly dismutates either spontaneously or enzymatically (via superoxide dismutase) into hydrogen peroxide (H2O2), or in the presence of iron or copper salts, it may form the hydroxyl free radical (HO●). Whilst O2- is relatively inactive, in the presence of nitric oxide it can form peroxynitrite (ONOO-), a highly reactive oxygen species ADDIN EN.CITE <EndNote><Cite><Author>Mittal</Author><Year>2014</Year><RecNum>64</RecNum><DisplayText>[24]</DisplayText><record><rec-number>64</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1508426635">64</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mittal, M.</author><author>Siddiqui, M. R.</author><author>Tran, K.</author><author>Reddy, S. P.</author><author>Malik, A. B.</author></authors></contributors><auth-address>1 Department of Pharmacology, Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois.</auth-address><titles><title>Reactive oxygen species in inflammation and tissue injury</title><secondary-title>Antioxid Redox Signal</secondary-title><alt-title>Antioxidants & redox signaling</alt-title></titles><periodical><full-title>Antioxid Redox Signal</full-title><abbr-1>Antioxidants & redox signaling</abbr-1></periodical><alt-periodical><full-title>Antioxid Redox Signal</full-title><abbr-1>Antioxidants & redox signaling</abbr-1></alt-periodical><pages>1126-67</pages><volume>20</volume><number>7</number><edition>2013/09/03</edition><keywords><keyword>Animals</keyword><keyword>Endothelium, Vascular/metabolism/*pathology</keyword><keyword>Humans</keyword><keyword>Inflammation/metabolism/*pathology</keyword><keyword>Neutrophils/metabolism/pathology</keyword><keyword>Oxidative Stress/physiology</keyword><keyword>Reactive Oxygen Species/*metabolism</keyword></keywords><dates><year>2014</year><pub-dates><date>Mar 01</date></pub-dates></dates><isbn>1557-7716 (Electronic)
1523-0864 (Linking)</isbn><accession-num>23991888</accession-num><work-type>Research Support, N.I.H., Extramural
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ADDIN EN.CITE.DATA [25,26]. Hydrogen peroxide is membrane-permeable, microbiocidal at high concentrations, and the major substrate of myeloperoxidase, a neutrophil granule enzyme implicated in the production of highly-reactive, secondary oxidants. Despite the generation of acidic compounds during the respiratory burst, the pH within the phagosome remains within the range of pH 7.5-8 and may, on occasions, rise as high as pH 9PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZXZpbmU8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS
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Tm90ZT5=
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Tm90ZT5=
ADDIN EN.CITE.DATA [27]. Protons are consumed during the formation of H2O2 and HO●, and K+ ions are actively pumped into the phagosome by calcium-activated K+ channels to compensate for the influx of electrons during NOX2 activity. This results in a transient increase in local pH, and a hypertonic K+-rich environment, which provides an optimal environment for the activity of granule proteases, such as elastase and cathepsin GPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZXZpbmU8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [27,28].Myeloperoxidase derived oxidants The major source of neutrophil secondary oxidants is via the action of myeloperoxidase (MPO), a haem peroxidase stored within azurophilic neutrophil granulesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OYXVzZWVmPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48
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ADDIN EN.CITE.DATA [29]. MPO catalyses the oxididation of halides (Cl-, Br-) and thiocyanate (SCN-) by H2O2 into hypochlorous (HOCl), hypobromous (HOBr), hypothiocyanous (HOSCN) acids (Figure 1), all of which have potent microbiocidal properties including chemical modification of proteins, lipids and DNA. For example, HOCl and HOBr react with methionine and cysteine residues to produce methionine sulfoxide and disulfides, promoting irreversible cross-linking in and between protein molecules, and also between DNA and proteinPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb25zZWluPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48
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ADDIN EN.CITE.DATA [30]. HOCl oxidizes DNA bases to form 5-hydroxyluracil, 5-hydroxycytosine, and thymine glycol ADDIN EN.CITE <EndNote><Cite><Author>Whiteman</Author><Year>1997</Year><RecNum>258</RecNum><DisplayText>[31]</DisplayText><record><rec-number>258</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511351980">258</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Whiteman, M.</author><author>Jenner, A.</author><author>Halliwell, B.</author></authors></contributors><auth-address>International Antioxidant Research Centre, University of London, Kings College, England. MATT.WHITEMAN@kcl.ac.uk</auth-address><titles><title>Hypochlorous acid-induced base modifications in isolated calf thymus DNA</title><secondary-title>Chem Res Toxicol</secondary-title></titles><periodical><full-title>Chem Res Toxicol</full-title><abbr-1>Chemical research in toxicology</abbr-1></periodical><pages>1240-6</pages><volume>10</volume><number>11</number><keywords><keyword>Animals</keyword><keyword>Cattle</keyword><keyword>DNA/*chemistry</keyword><keyword>DNA Damage</keyword><keyword>Gas Chromatography-Mass Spectrometry</keyword><keyword>Hydrogen-Ion Concentration</keyword><keyword>Hypochlorous Acid/*chemistry</keyword><keyword>Kinetics</keyword><keyword>Metals/chemistry</keyword><keyword>Oxidation-Reduction</keyword><keyword>Thymus Gland/*chemistry</keyword><keyword>Uracil/analogs & derivatives/chemistry</keyword></keywords><dates><year>1997</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>0893-228X (Print)
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ADDIN EN.CITE.DATA [35], and is implicated in DNA damage and modification of histones associated with inflammatory disease ADDIN EN.CITE <EndNote><Cite><Author>Kang</Author><Year>2008</Year><RecNum>30</RecNum><DisplayText>[36]</DisplayText><record><rec-number>30</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1507554846">30</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kang, J. I., Jr.</author><author>Neidigh, J. W.</author></authors></contributors><auth-address>Department of Basic Sciences, Biochemistry Division, Loma Linda University, School of Medicine, Loma Linda, California 92350, USA. jneidigh@llu.edu</auth-address><titles><title>Hypochlorous acid damages histone proteins forming 3-chlorotyrosine and 3,5-dichlorotyrosine</title><secondary-title>Chem Res Toxicol</secondary-title><alt-title>Chemical research in toxicology</alt-title></titles><periodical><full-title>Chem Res Toxicol</full-title><abbr-1>Chemical research in toxicology</abbr-1></periodical><alt-periodical><full-title>Chem Res Toxicol</full-title><abbr-1>Chemical research in toxicology</abbr-1></alt-periodical><pages>1028-38</pages><volume>21</volume><number>5</number><edition>2008/05/03</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Chlorine/chemistry</keyword><keyword>Histones/chemistry/isolation & purification/*metabolism</keyword><keyword>Hypochlorous Acid/*pharmacology</keyword><keyword>Mass Spectrometry</keyword><keyword>Molecular Sequence Data</keyword><keyword>Tyrosine/*analogs & derivatives/chemistry/metabolism</keyword></keywords><dates><year>2008</year><pub-dates><date>May</date></pub-dates></dates><isbn>1520-5010 (Electronic)
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ADDIN EN.CITE.DATA [24,38]. Xanthine oxidase reactions may also produce ROS, particularly under conditions of hypoxia which are often associated with inflammatory disease ADDIN EN.CITE <EndNote><Cite><Author>Mittal</Author><Year>2014</Year><RecNum>64</RecNum><DisplayText>[24]</DisplayText><record><rec-number>64</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1508426635">64</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mittal, M.</author><author>Siddiqui, M. R.</author><author>Tran, K.</author><author>Reddy, S. P.</author><author>Malik, A. B.</author></authors></contributors><auth-address>1 Department of Pharmacology, Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, Illinois.</auth-address><titles><title>Reactive oxygen species in inflammation and tissue injury</title><secondary-title>Antioxid Redox Signal</secondary-title><alt-title>Antioxidants & redox signaling</alt-title></titles><periodical><full-title>Antioxid Redox Signal</full-title><abbr-1>Antioxidants & redox signaling</abbr-1></periodical><alt-periodical><full-title>Antioxid Redox Signal</full-title><abbr-1>Antioxidants & redox signaling</abbr-1></alt-periodical><pages>1126-67</pages><volume>20</volume><number>7</number><edition>2013/09/03</edition><keywords><keyword>Animals</keyword><keyword>Endothelium, Vascular/metabolism/*pathology</keyword><keyword>Humans</keyword><keyword>Inflammation/metabolism/*pathology</keyword><keyword>Neutrophils/metabolism/pathology</keyword><keyword>Oxidative Stress/physiology</keyword><keyword>Reactive Oxygen Species/*metabolism</keyword></keywords><dates><year>2014</year><pub-dates><date>Mar 01</date></pub-dates></dates><isbn>1557-7716 (Electronic)
1523-0864 (Linking)</isbn><accession-num>23991888</accession-num><work-type>Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
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ADDIN EN.CITE.DATA [39]. Whilst H2O2 is a key substrate for MPO, it may also be metabolised by catalase and other peroxidases, including glutathione peroxidase, all of which transform H2O2 into H2O. However, superoxide dismutase, catalase and glutathione peroxidase may be inactivated if HOCl is present as a result of MPO reactions ADDIN EN.CITE <EndNote><Cite><Author>Aruoma</Author><Year>1987</Year><RecNum>61</RecNum><DisplayText>[40]</DisplayText><record><rec-number>61</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1508423517">61</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Aruoma, O. I.</author><author>Halliwell, B.</author></authors></contributors><auth-address>Department of Biochemistry, University of London King's College, Strand Campus, U.K.</auth-address><titles><title>Action of hypochlorous acid on the antioxidant protective enzymes superoxide dismutase, catalase and glutathione peroxidase</title><secondary-title>Biochem J</secondary-title><alt-title>The Biochemical journal</alt-title></titles><periodical><full-title>Biochem J</full-title><abbr-1>The Biochemical journal</abbr-1></periodical><alt-periodical><full-title>Biochem J</full-title><abbr-1>The Biochemical journal</abbr-1></alt-periodical><pages>973-6</pages><volume>248</volume><number>3</number><edition>1987/12/15</edition><keywords><keyword>Blood Proteins/pharmacology</keyword><keyword>Catalase/*antagonists & inhibitors</keyword><keyword>Glutathione Peroxidase/*antagonists & inhibitors</keyword><keyword>Hypochlorous Acid/*pharmacology</keyword><keyword>Pancreatic Elastase/antagonists & inhibitors</keyword><keyword>Superoxide Dismutase/*antagonists & inhibitors</keyword><keyword>alpha 1-Antitrypsin</keyword></keywords><dates><year>1987</year><pub-dates><date>Dec 15</date></pub-dates></dates><isbn>0264-6021 (Print)
0264-6021 (Linking)</isbn><accession-num>2829848</accession-num><work-type>Research Support, Non-U.S. Gov't</work-type><urls><related-urls><url>;[40]. Expression of anti-oxidant enzymes including superoxide dismutase and glutathione peroxidase is under the control of antioxidant response elements ADDIN EN.CITE <EndNote><Cite><Author>Chiu</Author><Year>2017</Year><RecNum>66</RecNum><DisplayText>[41]</DisplayText><record><rec-number>66</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1508427168">66</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chiu, A. V.</author><author>Saigh, M. A.</author><author>McCulloch, C. A.</author><author>Glogauer, M.</author></authors></contributors><auth-address>1 Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada.</auth-address><titles><title>The Role of NrF2 in the Regulation of Periodontal Health and Disease</title><secondary-title>J Dent Res</secondary-title><alt-title>Journal of dental research</alt-title></titles><periodical><full-title>J Dent Res</full-title><abbr-1>Journal of dental research</abbr-1></periodical><alt-periodical><full-title>J Dent Res</full-title><abbr-1>Journal of dental research</abbr-1></alt-periodical><pages>975-983</pages><volume>96</volume><number>9</number><edition>2017/06/16</edition><keywords><keyword>Animals</keyword><keyword>Antioxidants/physiology</keyword><keyword>Humans</keyword><keyword>*Immunity, Innate</keyword><keyword>NF-E2-Related Factor 2/*immunology</keyword><keyword>Neutrophils/immunology</keyword><keyword>Oxidative Stress/immunology</keyword><keyword>Periodontal Diseases/*immunology</keyword><keyword>antioxidant regulation</keyword><keyword>innate immunity</keyword><keyword>neutrophils</keyword><keyword>periodontitis</keyword><keyword>redox balance</keyword><keyword>transcriptional regulation</keyword></keywords><dates><year>2017</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1544-0591 (Electronic)
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ADDIN EN.CITE.DATA [42]. Redox factor-1 can be oxidised by ROS and translocate to the nucleus, where it interacts with thioredoxin and activates key transcription factors, including activator protein 1 (AP-1) and NF-κBPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XZWk8L0F1dGhvcj48WWVhcj4yMDAwPC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA [43]. The phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway can also be activated by ROS, through oxidation and inactivation of phosphatase and tensin homolog (PTEN), a phosphatase which dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate (PIP3) to phosphatidylinositol 4,5-bisphosphate (PIP2), normally inhibiting the signal transduction from PI3K and subsequent activation of pleckstrin homology domain containing proteins, such as 3-phosphoinositide-dependent protein kinase-1 (PDK-1) and protein kinase B (AKT)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TZW88L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA [49,50], TNFα ADDIN EN.CITE <EndNote><Cite><Author>Cross</Author><Year>2008</Year><RecNum>282</RecNum><DisplayText>[51]</DisplayText><record><rec-number>282</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1519652493">282</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cross, A.</author><author>Moots, R. J.</author><author>Edwards, S. W.</author></authors></contributors><auth-address>School of Biological Sciences, University of Liverpool, UK.</auth-address><titles><title>The dual effects of TNFalpha on neutrophil apoptosis are mediated via differential effects on expression of Mcl-1 and Bfl-1</title><secondary-title>Blood</secondary-title><alt-title>Blood</alt-title></titles><periodical><full-title>Blood</full-title><abbr-1>Blood</abbr-1></periodical><alt-periodical><full-title>Blood</full-title><abbr-1>Blood</abbr-1></alt-periodical><pages>878-84</pages><volume>111</volume><number>2</number><keywords><keyword>Apoptosis/*drug effects/physiology</keyword><keyword>Cell Survival/drug effects/physiology</keyword><keyword>Dose-Response Relationship, Drug</keyword><keyword>Gene Expression Regulation/*drug effects/physiology</keyword><keyword>Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology</keyword><keyword>Humans</keyword><keyword>Neoplasm Proteins/*biosynthesis</keyword><keyword>Neutrophils/cytology/*metabolism</keyword><keyword>Proto-Oncogene Proteins c-bcl-2/*biosynthesis</keyword><keyword>Transcription, Genetic/drug effects/physiology</keyword><keyword>Tumor Necrosis Factor-alpha/metabolism/*pharmacology</keyword></keywords><dates><year>2008</year><pub-dates><date>Jan 15</date></pub-dates></dates><isbn>0006-4971 (Print)</isbn><accession-num>17942758</accession-num><urls><related-urls><url> </url></related-urls></urls><language>eng</language></record></Cite></EndNote>[51], leukotriene B4PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZXRyaW48L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [50,51,54]. Leukotriene B4-delayed apoptosis has been shown to be NOX2-generated ROS dependentPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJjZWxsb3MtZGUtU291emE8L0F1dGhvcj48WWVhcj4y
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYXJjZWxsb3MtZGUtU291emE8L0F1dGhvcj48WWVhcj4y
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AG==
ADDIN EN.CITE.DATA [55]. Following phagocytosis neutrophils initiate a specialised programme of cell death termed phagocytosis-induced cell death. During phagocytosis-induced cell death, neutrophils up-regulate expression of phosphatidylserine on their extracellular membrane as an “eat me” signal to initiate removal by nearby macrophagesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYW1wdG9uPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48
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ADDIN EN.CITE.DATA [57-59]. This mixture of pro- and anti-apoptotic signals ensures maximal phagocytosis of pathogens prior to phagocytosis-induced cell death. There is mounting evidence that phagocytosis-induced cell death is regulated by NOX2-derived ROS, and that intracellular concentrations of ROS may influence regulators of apoptosis. GM-CSF both increases ROS production and delays apoptosis in phagocytosing neutrophilsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFuZzwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [60]. During phagocytosis of S. aureus, NOX2-derived ROS prevents activation of caspase-3, delaying apoptosisPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxraWU8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [56,61]. The NOX2 inhibitor diphenyleneiodonium decreases expression of phosphatidylserine on the surface of neutrophils, and prevents phagocytosis by macrophagesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYW1wdG9uPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48
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ADDIN EN.CITE.DATA [56]. NETosisNeutrophil extracellular traps (NETs) are mesh like DNA structures decorated with histones, MPO and other antimicrobial proteins expelled from neutrophils in response to infectious or inflammatory stimuliPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccmlua21hbm48L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFy
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ADDIN EN.CITE.DATA [69,72,73]. Calcium ionophores such as ionomycin and A23187 induce the release NETs, and in particular, citrullinated histones on NETsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OZWVsaTwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [65-68]. Several physiological agonists have also been reported to induce NET release, including fMLP, IL-8, lipopolysaccharide, nitric oxide, TNFα and others ADDIN EN.CITE <EndNote><Cite><Author>Rohrbach</Author><Year>2012</Year><RecNum>236</RecNum><DisplayText>[74]</DisplayText><record><rec-number>236</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511351979">236</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rohrbach, A. S.</author><author>Slade, D. J.</author><author>Thompson, P. R.</author><author>Mowen, K. A.</author></authors></contributors><auth-address>Department of Chemical Physiology, The Scripps Research Institute La Jolla, CA, USA.</auth-address><titles><title>Activation of PAD4 in NET formation</title><secondary-title>Front Immunol</secondary-title></titles><periodical><full-title>Front Immunol</full-title></periodical><pages>360</pages><volume>3</volume><keywords><keyword>Net</keyword><keyword>Pad4</keyword><keyword>citrullination</keyword><keyword>deimination</keyword><keyword>neutrophil</keyword></keywords><dates><year>2012</year></dates><isbn>1664-3224 (Electronic)
1664-3224 (Linking)</isbn><accession-num>23264775</accession-num><urls><related-urls><url>;[74]. ROS production is required for several steps of NET formation, causing increases in membrane permeability and release of neutrophil elastase from granules, which in turn degrades the linker histone H1 and the core histones, driving chromatin decondensation ADDIN EN.CITE <EndNote><Cite><Author>Papayannopoulos</Author><Year>2010</Year><RecNum>245</RecNum><DisplayText>[75]</DisplayText><record><rec-number>245</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511351980">245</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Papayannopoulos, V.</author><author>Metzler, K. D.</author><author>Hakkim, A.</author><author>Zychlinsky, A.</author></authors></contributors><auth-address>Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin, Germany.</auth-address><titles><title>Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps</title><secondary-title>J Cell Biol</secondary-title></titles><periodical><full-title>J Cell Biol</full-title><abbr-1>The Journal of cell biology</abbr-1></periodical><pages>677-91</pages><volume>191</volume><number>3</number><keywords><keyword>Animals</keyword><keyword>Disease Models, Animal</keyword><keyword>Extracellular Space/*metabolism</keyword><keyword>Humans</keyword><keyword>Klebsiella Infections/immunology/microbiology</keyword><keyword>Klebsiella pneumoniae</keyword><keyword>Leukocyte Elastase/deficiency/*metabolism</keyword><keyword>Mice</keyword><keyword>Mice, Knockout</keyword><keyword>Neutrophils/*cytology/*enzymology/immunology</keyword><keyword>Peroxidase/*metabolism</keyword><keyword>Reference Values</keyword></keywords><dates><year>2010</year><pub-dates><date>Nov 01</date></pub-dates></dates><isbn>1540-8140 (Electronic)
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ADDIN EN.CITE.DATA [70] and inactivate caspases to block apoptosis and trigger autophagy ADDIN EN.CITE <EndNote><Cite><Author>Papayannopoulos</Author><Year>2010</Year><RecNum>245</RecNum><DisplayText>[75]</DisplayText><record><rec-number>245</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511351980">245</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Papayannopoulos, V.</author><author>Metzler, K. D.</author><author>Hakkim, A.</author><author>Zychlinsky, A.</author></authors></contributors><auth-address>Department of Cellular Microbiology, Max Planck Institute for Infection Biology, Berlin, Germany.</auth-address><titles><title>Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps</title><secondary-title>J Cell Biol</secondary-title></titles><periodical><full-title>J Cell Biol</full-title><abbr-1>The Journal of cell biology</abbr-1></periodical><pages>677-91</pages><volume>191</volume><number>3</number><keywords><keyword>Animals</keyword><keyword>Disease Models, Animal</keyword><keyword>Extracellular Space/*metabolism</keyword><keyword>Humans</keyword><keyword>Klebsiella Infections/immunology/microbiology</keyword><keyword>Klebsiella pneumoniae</keyword><keyword>Leukocyte Elastase/deficiency/*metabolism</keyword><keyword>Mice</keyword><keyword>Mice, Knockout</keyword><keyword>Neutrophils/*cytology/*enzymology/immunology</keyword><keyword>Peroxidase/*metabolism</keyword><keyword>Reference Values</keyword></keywords><dates><year>2010</year><pub-dates><date>Nov 01</date></pub-dates></dates><isbn>1540-8140 (Electronic)
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ADDIN EN.CITE.DATA [75-78]. Absence of extracellular Cl-, a substrate for MPO, decreases NET production in vitro, and whilst exogenous addition of H2O2 and HOCl stimulates NETosis, only exogenous HOCl can rescue NETosis in the setting of MPO inhibitionPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ba29uZy1Nb29yZTwvQXV0aG9yPjxZZWFyPjIwMTI8L1ll
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ADDIN EN.CITE.DATA [35]. NETosis induced by calcium ionophores such as A23187 appears to occur in a different manner from that of PMA-induced NETosis, and appears to be independent of NOX2 activity and thus is often referred to as NOX-independent NET formationPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb3VkYTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [81-85]. The main mechanism for this is through oxidation of sulphur-containing cysteine and methionine residues resulting in altered protein structure, function and DNA binding capacity. Cysteine thiols (-SH) are oxidised to sulfenic acid (-SOH), which can then form di-sulphide bonds or be further oxidised to sulfinic (-SO2H) and sulfonic acid (-SO3H), with increasing irreversibility, whereas methionine sulphides (-SR) are oxidised to sulfoxide (-SOR), and further to sulfonyl (-SO2R). These reactions are largely reversible, with a primary act of ROS signalling being their own regulation, or oxidative homeostasis: as ROS levels increase, mechanisms to reduce ROS and return to an equilibrated state are activated. Dedicated reductase enzymes reduce the oxidised residues back to their normal state, whilst a plethora of antioxidant mechanisms act to scavenge loose oxidants and prevent damage.Mitogen-activated protein kinases (MAPK) respond to ROS in a cell type and stimulus specific manner ADDIN EN.CITE <EndNote><Cite><Author>Iles</Author><Year>2002</Year><RecNum>130</RecNum><DisplayText>[85]</DisplayText><record><rec-number>130</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511273531">130</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Iles, K. E.</author><author>Forman, H. J.</author></authors></contributors><auth-address>Department of Environmental Health Sciences, School of Public Health, and Center for Free Radical Biology, University of Alabama at Birmingham, 35294-0022, USA.</auth-address><titles><title>Macrophage signaling and respiratory burst</title><secondary-title>Immunol Res</secondary-title><alt-title>Immunologic research</alt-title></titles><periodical><full-title>Immunol Res</full-title><abbr-1>Immunologic research</abbr-1></periodical><alt-periodical><full-title>Immunol Res</full-title><abbr-1>Immunologic research</abbr-1></alt-periodical><pages>95-105</pages><volume>26</volume><number>1-3</number><edition>2002/10/31</edition><keywords><keyword>Animals</keyword><keyword>Enzyme Activation</keyword><keyword>Humans</keyword><keyword>JNK Mitogen-Activated Protein Kinases</keyword><keyword>MAP Kinase Signaling System</keyword><keyword>Macrophages, Alveolar/*immunology/*metabolism</keyword><keyword>Mitogen-Activated Protein Kinases/metabolism</keyword><keyword>NADPH Oxidase/metabolism</keyword><keyword>NF-kappa B/metabolism</keyword><keyword>Reactive Oxygen Species/metabolism</keyword><keyword>Respiratory Burst</keyword><keyword>Signal Transduction</keyword></keywords><dates><year>2002</year></dates><isbn>0257-277X (Print)
0257-277x</isbn><accession-num>12403349</accession-num><urls></urls><electronic-resource-num>10.1385/ir:26:1-3:095</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[85]. In neutrophils, endogenous production of H2O2 is regulated by p38-MAPK and c-Jun n-terminal kinase (JNK) and, and can induce phosphorylation of ERK1/2 ADDIN EN.CITE <EndNote><Cite><Author>Petropoulos</Author><Year>2015</Year><RecNum>137</RecNum><DisplayText>[86]</DisplayText><record><rec-number>137</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511273531">137</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Petropoulos, Michalis</author><author>Karamolegkou, Georgia</author><author>Rosmaraki, Eleftheria</author><author>Tsakas, Sotiris</author></authors></contributors><titles><title>Hydrogen peroxide signals E. coli phagocytosis by human polymorphonuclear cells; up-stream and down-stream pathway</title><secondary-title>Redox Biology</secondary-title></titles><periodical><full-title>Redox Biol</full-title><abbr-1>Redox biology</abbr-1></periodical><pages>100-105</pages><volume>6</volume><dates><year>2015</year><pub-dates><date>07/14
06/16/received
07/09/revised
07/10/accepted</date></pub-dates></dates><publisher>Elsevier</publisher><isbn>2213-2317</isbn><accession-num>PMC4804100</accession-num><urls><related-urls><url>;[86]. The apoptosis signal-related kinase 1 (ASK1) is activated by ROS, causing dissociation of thioredoxin and subsequent oxidation of Cys-32 and Cys-35 followed by formation of a di-sulphide bondPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TYWl0b2g8L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [89]. Several ROS-activated protein kinase families, including protein kinases -A, -C and -G, have been implicated in MAPK signalling ADDIN EN.CITE <EndNote><Cite><Author>Ray</Author><Year>2012</Year><RecNum>141</RecNum><DisplayText>[90]</DisplayText><record><rec-number>141</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511273531">141</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ray, P. D.</author><author>Huang, B. W.</author><author>Tsuji, Y.</author></authors></contributors><auth-address>Department of Environmental and Molecular Toxicology, North Carolina State University, Campus Box 7633, Raleigh, NC 27695-7633, USA.</auth-address><titles><title>Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling</title><secondary-title>Cell Signal</secondary-title><alt-title>Cellular signalling</alt-title></titles><periodical><full-title>Cell Signal</full-title><abbr-1>Cellular signalling</abbr-1></periodical><alt-periodical><full-title>Cell Signal</full-title><abbr-1>Cellular signalling</abbr-1></alt-periodical><pages>981-90</pages><volume>24</volume><number>5</number><edition>2012/01/31</edition><keywords><keyword>Amino Acid Sequence</keyword><keyword>Animals</keyword><keyword>Gene Expression Regulation</keyword><keyword>*Homeostasis</keyword><keyword>Humans</keyword><keyword>Intracellular Signaling Peptides and Proteins/metabolism/physiology</keyword><keyword>Molecular Sequence Data</keyword><keyword>Oxidation-Reduction</keyword><keyword>Oxidative Stress</keyword><keyword>Reactive Oxygen Species/*metabolism</keyword><keyword>*Signal Transduction</keyword></keywords><dates><year>2012</year><pub-dates><date>May</date></pub-dates></dates><isbn>0898-6568</isbn><accession-num>22286106</accession-num><urls></urls><custom2>PMC3454471</custom2><custom6>NIHMS351530</custom6><electronic-resource-num>10.1016/j.cellsig.2012.01.008</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[90]. Inhibition of MAPK phosphatases by ROS can also modulate MAPK activity. Oxidation of many protein tyrosine phosphatases blocks their ability to inhibit MAPK activationPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MaXU8L0F1dGhvcj48WWVhcj4yMDEwPC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA [94].Specifically in neutrophils, ROS are implicated in migration to and from wounds and may be necessary for resolution of neutrophil-mediated inflammation. The Src family kinase Lyn acts as a sensor for H2O2 gradients, generated from epithelial wounds by dual oxidase, attracting neutrophils to the site of injuryPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UYXV6aW48L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [95]. Adhesion molecule expression can also be sensitive to the ROS environment. Adhesion of neutrophils to endothelial cells, and subsequent extravasation into tissues, involves ROS-induced phosphorylation of focal adhesion kinase pp125FAK, paxillin and p130casPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb3ppbjwvQXV0aG9yPjxZZWFyPjE5OTg8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [96].Neutrophil oxidants in autoimmune diseaseRheumatoid arthritis Rheumatoid arthritis (RA) is an inflammatory disease of the joints which causes irreversible damage to synovial tissues, including degradation of cartilage and underlying bone. The disease is characterised by the growth of a hyperplastic inflammatory tissue (pannus) within the joint, which is enriched with synovial fibroblasts and leukocytes that drive the inflammatory process. Neutrophils have long been implicated in the pathogenesis of RA due to their ability to release inflammatory cytokines, ROS and matrix proteases via the secretome. In RA, immune complexes such as rheumatoid factor and anti-citrullinated protein antibodies activate neutrophils via Fc receptorsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2JpbnNvbjwvQXV0aG9yPjxZZWFyPjE5OTQ8L1llYXI+
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ADDIN EN.CITE.DATA [97]. This triggers neutrophils to degranulate either into the synovial fluid or directly onto the articular surface forming a microenvironment of concentrated ROS, proteases and cytotoxic factors ADDIN EN.CITE <EndNote><Cite><Author>Wright</Author><Year>2014</Year><RecNum>104</RecNum><DisplayText>[8]</DisplayText><record><rec-number>104</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1510658313">104</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wright, Helen L</author><author>Moots, Robert J</author><author>Edwards, Steven W</author></authors></contributors><titles><title>The multifactorial role of neutrophils in rheumatoid arthritis.</title><secondary-title>Nature Reviews Rheumatology</secondary-title></titles><periodical><full-title>Nature Reviews Rheumatology</full-title></periodical><pages>593-601</pages><volume>10</volume><number>10</number><dates><year>2014</year></dates><publisher>Nature Publishing Group</publisher><accession-num>24914698</accession-num><urls></urls><electronic-resource-num>10.1038/nrrheum.2014.80</electronic-resource-num></record></Cite></EndNote>[8]. These processes result in a heightened presence of ROS in the joint environment, causing damage to the articular cartilage and underlying bone ADDIN EN.CITE <EndNote><Cite><Author>Wright</Author><Year>2014</Year><RecNum>104</RecNum><DisplayText>[8]</DisplayText><record><rec-number>104</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1510658313">104</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wright, Helen L</author><author>Moots, Robert J</author><author>Edwards, Steven W</author></authors></contributors><titles><title>The multifactorial role of neutrophils in rheumatoid arthritis.</title><secondary-title>Nature Reviews Rheumatology</secondary-title></titles><periodical><full-title>Nature Reviews Rheumatology</full-title></periodical><pages>593-601</pages><volume>10</volume><number>10</number><dates><year>2014</year></dates><publisher>Nature Publishing Group</publisher><accession-num>24914698</accession-num><urls></urls><electronic-resource-num>10.1038/nrrheum.2014.80</electronic-resource-num></record></Cite></EndNote>[8]. Patients with RA have evidence of increased ROS production in their circulating blood and synovium, with several studies demonstrating a significant correlation between ROS levels and disease activityPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb29kbGV5PC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48
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ADDIN EN.CITE.DATA [104].Markers of ROS-mediated damage, including lipid peroxidation, protein oxidation and DNA damage are increased in RA blood, whereas antioxidant defence mechanisms, both enzymatic such as catalase and superoxide dismutase, and non-enzymatic such as vitamin C and reduced glutathione, are retarded ADDIN EN.CITE <EndNote><Cite><Author>Mateen</Author><Year>2016</Year><RecNum>86</RecNum><DisplayText>[105]</DisplayText><record><rec-number>86</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1510653380">86</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mateen, Somaiya</author><author>Moin, Shagufta</author><author>Khan, Abdul Qayyum</author><author>Zafar, Atif</author><author>Fatima, Naureen</author></authors></contributors><titles><title>Increased Reactive Oxygen Species Formation and Oxidative Stress in Rheumatoid Arthritis</title><secondary-title>PLOS ONE</secondary-title></titles><periodical><full-title>PLoS One</full-title><abbr-1>PloS one</abbr-1></periodical><pages>e0152925</pages><volume>11</volume><number>4</number><dates><year>2016</year></dates><publisher>Public Library of Science</publisher><urls><related-urls><url>;[105]. Antioxidants have a demonstrable effect on lowering ROS production in ex vivo neutrophils and on in vitro matrix degradationPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2NoaTwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [106,107], and oxidative stress within RA synovial tissues decreases during therapy, such as with TNF-α inhibitors ADDIN EN.CITE <EndNote><Cite><Author>Biniecka</Author><Year>2011</Year><RecNum>71</RecNum><DisplayText>[108]</DisplayText><record><rec-number>71</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1510653380">71</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Biniecka, Monika</author><author>Kennedy, Aisling</author><author>Ng, Chin T.</author><author>Chang, Ting C.</author><author>Balogh, Emese</author><author>Fox, Edward</author><author>Veale, Douglas J.</author><author>Fearon, Ursula</author><author>O'Sullivan, Jacintha N.</author></authors></contributors><titles><title>Successful tumour necrosis factor (TNF) blocking therapy suppresses oxidative stress and hypoxia-induced mitochondrial mutagenesis in inflammatory arthritis</title><secondary-title>Arthritis Research & Therapy</secondary-title></titles><periodical><full-title>Arthritis Res Ther</full-title><abbr-1>Arthritis research & therapy</abbr-1></periodical><pages>R121-R121</pages><volume>13</volume><number>4</number><dates><year>2011</year><pub-dates><date>07/25
03/16/received
06/02/revised
07/25/accepted</date></pub-dates></dates><publisher>BioMed Central</publisher><isbn>1478-6354
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ADDIN EN.CITE.DATA [109-111]. Dysfunctional immunoglobulin G (IgG), can be found in the sera of patients with RA. ROS-mediated modification of human IgG generates novel antigens and increases immunogenicity and production of rheumatoid factor immune complexes ADDIN EN.CITE <EndNote><Cite><Author>Rasheed</Author><Year>2008</Year><RecNum>95</RecNum><DisplayText>[112]</DisplayText><record><rec-number>95</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1510653380">95</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rasheed, Z.</author></authors></contributors><auth-address>Department of Biochemistry, Faculty of Medicine, A.M.U., Aligarh-202002, U.P., India. zrasheed@</auth-address><titles><title>Hydroxyl radical damaged immunoglobulin G in patients with rheumatoid arthritis: biochemical and immunological studies</title><secondary-title>Clin Biochem</secondary-title><alt-title>Clinical biochemistry</alt-title></titles><periodical><full-title>Clin Biochem</full-title><abbr-1>Clinical biochemistry</abbr-1></periodical><alt-periodical><full-title>Clinical Biochemistry</full-title></alt-periodical><pages>663-9</pages><volume>41</volume><number>9</number><edition>2008/03/25</edition><keywords><keyword>Adult</keyword><keyword>Animals</keyword><keyword>Arthritis, Rheumatoid/*immunology/*metabolism</keyword><keyword>Autoantibodies/biosynthesis/blood</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Hydroxyl Radical/*adverse effects</keyword><keyword>Immunoglobulin G/adverse effects/*metabolism/physiology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Rabbits</keyword><keyword>Reactive Oxygen Species/adverse effects</keyword></keywords><dates><year>2008</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0009-9120</isbn><accession-num>18359293</accession-num><urls></urls><electronic-resource-num>10.1016/j.clinbiochem.2008.02.013</electronic-resource-num><remote-database-provider>NLM</remote-database-provider><language>eng</language></record></Cite></EndNote>[112]. Both soluble and synovial tissue embedded complexes of IgG are the main activator of ROS release by RA neutrophils, acting via FcγR2a and FcγR3bPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3NzYXRpPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48
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ADDIN EN.CITE.DATA [113]. Complexes of soluble IgG stimulate the extracellular release of O2- and H2O2 species in vitro from neutrophils primed with cytokines such as GM-CSF and TNFPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3NzYXRpPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48
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ADDIN EN.CITE.DATA [113]. This extracellular release of ROS is due almost entirely to activation of neutrophils via FcγR3bPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3NzYXRpPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48
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ADDIN EN.CITE.DATA [114]. Interestingly, removal or blockade of FcγR3b does not impact significantly on bacterial phagocytosis and killing, identifying this receptor as a potential, ROS-specific therapeutic target in RAPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3NzYXRpPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48
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ADDIN EN.CITE.DATA [114].Whilst ROS production in the joint can act directly to modify, denature and breakdown cell and matrix components, increasing levels in the joint environment can also disrupt oxidative homeostasis and induce ROS-mediated signalling pathways in both neutrophils and surrounding cells. Regulation of matrix metalloproteinasesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXJraGFyZHQ8L0F1dGhvcj48WWVhcj4xOTg2PC9ZZWFy
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ADDIN EN.CITE.DATA [115,116], collagen degradation ADDIN EN.CITE <EndNote><Cite><Author>Monboisse</Author><Year>1983</Year><RecNum>106</RecNum><DisplayText>[107]</DisplayText><record><rec-number>106</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1510659968">106</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Monboisse, J. C.</author><author>Braquet, P.</author><author>Randoux, A.</author><author>Borel, J. P.</author></authors></contributors><titles><title>Non-enzymatic degradation of acid-soluble calf skin collagen by superoxide ion: protective effect of flavonoids</title><secondary-title>Biochem Pharmacol</secondary-title><alt-title>Biochemical pharmacology</alt-title></titles><periodical><full-title>Biochem Pharmacol</full-title><abbr-1>Biochemical pharmacology</abbr-1></periodical><alt-periodical><full-title>Biochem Pharmacol</full-title><abbr-1>Biochemical pharmacology</abbr-1></alt-periodical><pages>53-8</pages><volume>32</volume><number>1</number><edition>1983/01/01</edition><keywords><keyword>Animals</keyword><keyword>Cattle</keyword><keyword>Collagen/*metabolism</keyword><keyword>Flavonoids/*pharmacology</keyword><keyword>Hydrolysis</keyword><keyword>Hydroxyproline/metabolism</keyword><keyword>Oxygen/*metabolism</keyword><keyword>Skin</keyword><keyword>Superoxides/*metabolism</keyword><keyword>Time Factors</keyword></keywords><dates><year>1983</year><pub-dates><date>Jan 01</date></pub-dates></dates><isbn>0006-2952 (Print)
0006-2952 (Linking)</isbn><accession-num>6299298</accession-num><work-type>Research Support, Non-U.S. Gov't</work-type><urls><related-urls><url>;[107], fibronectin fragment formation ADDIN EN.CITE <EndNote><Cite><Author>Homandberg</Author><Year>1998</Year><RecNum>84</RecNum><DisplayText>[117]</DisplayText><record><rec-number>84</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1510653380">84</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Homandberg, Gene A.</author><author>Wen, Catherine</author><author>Hui, Francis</author></authors></contributors><titles><title>Cartilage damaging activities of fibronectin fragments derived from cartilage and synovial fluid</title><secondary-title>Osteoarthritis and Cartilage</secondary-title></titles><periodical><full-title>Osteoarthritis and Cartilage</full-title></periodical><pages>231-244</pages><volume>6</volume><number>4</number><keywords><keyword>Fibronectin, Cartilage, Fragments, Proteases, Damage, Proteoglycan.</keyword></keywords><dates><year>1998</year><pub-dates><date>1998/07/01/</date></pub-dates></dates><isbn>1063-4584</isbn><urls><related-urls><url>;[117] and chondrocyte hypertrophy and apoptosis ADDIN EN.CITE <EndNote><Cite><Author>Morita</Author><Year>2007</Year><RecNum>92</RecNum><DisplayText>[118]</DisplayText><record><rec-number>92</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1510653380">92</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Morita, Kozo</author><author>Miyamoto, Takeshi</author><author>Fujita, Nobuyuki</author><author>Kubota, Yoshiaki</author><author>Ito, Keisuke</author><author>Takubo, Keiyo</author><author>Miyamoto, Kana</author><author>Ninomiya, Ken</author><author>Suzuki, Toru</author><author>Iwasaki, Ryotaro</author><author>Yagi, Mitsuru</author><author>Takaishi, Hironari</author><author>Toyama, Yoshiaki</author><author>Suda, Toshio</author></authors></contributors><titles><title>Reactive oxygen species induce chondrocyte hypertrophy in endochondral ossification</title><secondary-title>The Journal of Experimental Medicine</secondary-title></titles><periodical><full-title>The Journal of Experimental Medicine</full-title></periodical><pages>1613</pages><volume>204</volume><number>7</number><dates><year>2007</year></dates><work-type>10.1084/jem.20062525</work-type><urls><related-urls><url>;[118] can all be linked to ROS activity. Cyclooxygenase (COX)-2, an enzyme involved in pro-inflammatory prostaglandin synthesis and a common target of non-steriodal anti-inflammatory drugs, is highly expressed in RA and can be induced in synovial fibroblasts by ROS-induced MAPK and NF-κB activation via phosphorylation of transforming growth factor beta-activated kinase 1?(TAK1) ADDIN EN.CITE <EndNote><Cite><Author>Onodera</Author><Year>2015</Year><RecNum>94</RecNum><DisplayText>[119]</DisplayText><record><rec-number>94</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1510653380">94</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Onodera, Y.</author><author>Teramura, T.</author><author>Takehara, T.</author><author>Shigi, K.</author><author>Fukuda, K.</author></authors></contributors><auth-address>Division of Cell Biology for Regenerative Medicine, Institute of Advanced Clinical Medicine, Kindai University Faculty of Medicine, Osaka, Japan.</auth-address><titles><title>Reactive oxygen species induce Cox-2 expression via TAK1 activation in synovial fibroblast cells</title><secondary-title>FEBS Open Bio</secondary-title><alt-title>FEBS open bio</alt-title></titles><periodical><full-title>FEBS Open Bio</full-title><abbr-1>FEBS open bio</abbr-1></periodical><alt-periodical><full-title>FEBS Open Bio</full-title><abbr-1>FEBS open bio</abbr-1></alt-periodical><pages>492-501</pages><volume>5</volume><edition>2015/06/26</edition><keywords><keyword>COX, cyclooxygenase</keyword><keyword>Cox-2</keyword><keyword>HA, hyaluronic acid</keyword><keyword>NAC, N-acetyl cysteamine</keyword><keyword>OA model</keyword><keyword>OA, osteoarthritis</keyword><keyword>PGs, prostaglandins</keyword><keyword>RA, rheumatoid arthritis</keyword><keyword>ROS, reactive oxygen species</keyword><keyword>Reactive oxygen species</keyword><keyword>SFs, synovial fibroblast cells</keyword><keyword>Synovial tissues</keyword><keyword>Tak1</keyword></keywords><dates><year>2015</year></dates><isbn>2211-5463 (Print)
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ADDIN EN.CITE.DATA [120,121], and oxidative stress inhibits expression of IL-17 and interferon-γ in vitro and ex vivo in CD4+ T cells, suggesting a role for ROS in directing specific adaptive immune responses.Systemic lupus erythematosus Systemic lupus erythematosus?(SLE) is a heterogeneous autoimmune disease with chronic or episodic inflammation in several organ systems, including the skin, joints, central nervous system and kidneys. Patients are at increased risk of both cardiovascular events and subclinical atherosclerosis. SLE may be characterised by multiple autoantibodies, circulating immune complexes at high levels, and low complement levels. Many clinical manifestations of SLE, including organ damage, can be explained by the release of enzymes from neutrophil granules and increased production of ROS in response immune complexes deposited in tissuesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXVsPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVj
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AG==
ADDIN EN.CITE.DATA [125-127], and basal H2O2 production by SLE neutrophils is the highest in neutrophils from patients with lupus nephritis ADDIN EN.CITE <EndNote><Cite><Author>Perazzio</Author><Year>2012</Year><RecNum>176</RecNum><DisplayText>[127]</DisplayText><record><rec-number>176</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511342256">176</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Perazzio, S. F.</author><author>Salomao, R.</author><author>Silva, N. P.</author><author>Andrade, L. E.</author></authors></contributors><auth-address>Division of Rheumatology, UNIFESP/EPM, Sao Paulo, Brazil.</auth-address><titles><title>Increased neutrophil oxidative burst metabolism in systemic lupus erythematosus</title><secondary-title>Lupus</secondary-title></titles><periodical><full-title>Lupus</full-title></periodical><pages>1543-51</pages><volume>21</volume><number>14</number><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Case-Control Studies</keyword><keyword>Flow Cytometry</keyword><keyword>Fluoresceins/chemistry</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*physiopathology</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Neutrophils/*metabolism</keyword><keyword>Oxidation-Reduction</keyword><keyword>Phagocytes/*metabolism</keyword><keyword>Pseudomonas aeruginosa/metabolism</keyword><keyword>Reactive Oxygen Species/*metabolism</keyword><keyword>Severity of Illness Index</keyword><keyword>Staphylococcus aureus/metabolism</keyword><keyword>Young Adult</keyword></keywords><dates><year>2012</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1477-0962 (Electronic)
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ADDIN EN.CITE.DATA [128]. SLE disease course?varies between patients, with most patients experiencing both recurrent ‘active’ SLE flares and periods of ‘inactive’ disease. Neutrophils from SLE patients in active flare have been shown, paradoxically, to produce lower levels of ROS in vitro than neutrophils from SLE patients with inactive disease. However, ‘active SLE’ neutrophils exhibit higher levels of intracellular oxidative damage, including decreased levels of malondialdehyde, a marker of lipid peroxidation, and high levels of protein oxidation, evidenced by increased carbonyl groups and decreased thiol (SH) levels, suggesting exposure to oxidative stress in vivo prior to isolation from the bloodPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FbGxvdW1pPC9BdXRob3I+PFllYXI+MjAxNzwvWWVhcj48
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ADDIN EN.CITE.DATA [126]. Lower ROS production by ‘active SLE’ neutrophils in response to IgG immune complexes in vitro may be explained by lower expression of FcγRII (CD32) and complement receptor 1 (CR1)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJ6b2NjaGktTWFjaGFkbzwvQXV0aG9yPjxZZWFyPjIw
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ADDIN EN.CITE.DATA [130]. SLE serum induces O2- generation in healthy neutrophils, with O2- production correlating positively with the presence of immune complexes and negatively with complement levels ADDIN EN.CITE <EndNote><Cite><Author>Shingu</Author><Year>1983</Year><RecNum>188</RecNum><DisplayText>[131]</DisplayText><record><rec-number>188</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511342256">188</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shingu, M.</author><author>Oribe, M.</author><author>Todoroki, T.</author><author>Tatsukawa, K.</author><author>Tomo-oka, K.</author><author>Yasuda, M.</author><author>Nobunaga, M.</author></authors></contributors><titles><title>Serum factors from patients with systemic lupus erythematosus enhancing superoxide generation by normal neutrophils</title><secondary-title>J Invest Dermatol</secondary-title></titles><periodical><full-title>J Invest Dermatol</full-title><abbr-1>The Journal of investigative dermatology</abbr-1></periodical><pages>212-5</pages><volume>81</volume><number>3</number><keywords><keyword>Cytochrome c Group/blood</keyword><keyword>Freezing</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*blood/immunology</keyword><keyword>Neutrophils/*metabolism</keyword><keyword>Oxygen/*blood</keyword><keyword>Superoxide Dismutase/metabolism</keyword><keyword>Superoxides/*blood</keyword></keywords><dates><year>1983</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>0022-202X (Print)
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ADDIN EN.CITE.DATA [132]. The missense single nucleotide polymorphism, rs201802880, NCF1-339 T allele, decreases extracellular ROS release by SLE neutrophils but increases expression of type 1 interferon-regulated genes, and in addition is associated with a younger age of diagnosis. This suggests that ROS may be less important drivers of disease in individuals carrying this Ncf1 variantPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PbHNzb248L0F1dGhvcj48WWVhcj4yMDE3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [133]. Neutrophils from SLE patients exhibit markers of oxidative stress, including increased DNA damage ADDIN EN.CITE <EndNote><Cite><Author>McConnell</Author><Year>2002</Year><RecNum>180</RecNum><DisplayText>[134]</DisplayText><record><rec-number>180</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511342256">180</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McConnell, J. R.</author><author>Crockard, A. D.</author><author>Cairns, A. P.</author><author>Bell, A. L.</author></authors></contributors><auth-address>Queen's University Musculoskeletal Education and Research Unit, Department of Rheumatology, Musgrave Park Hospital, Belfast, UK.</auth-address><titles><title>Neutrophils from systemic lupus erythematosus patients demonstrate increased nuclear DNA damage</title><secondary-title>Clin Exp Rheumatol</secondary-title></titles><periodical><full-title>Clin Exp Rheumatol</full-title></periodical><pages>653-60</pages><volume>20</volume><number>5</number><keywords><keyword>Adult</keyword><keyword>Annexin A5/*analysis</keyword><keyword>Antibodies, Antinuclear/*analysis</keyword><keyword>*Apoptosis</keyword><keyword>Arthritis, Rheumatoid/*immunology/metabolism</keyword><keyword>Comet Assay</keyword><keyword>*DNA Fragmentation</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/*immunology/metabolism</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Neutrophils/*immunology/metabolism</keyword></keywords><dates><year>2002</year><pub-dates><date>Sep-Oct</date></pub-dates></dates><isbn>0392-856X (Print)
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ADDIN EN.CITE.DATA [136].Anti-phospholipid syndrome One third of SLE patients have anti-phospholipid syndrome (APS), the major clinical manifestation of which is thrombosis and/or pregnancy loss. The presence of one of these clinical features, plus anti-phospholipid antibodies such as anti-cardiolipin, anti-β2-glycoprotein-I or lupus antibody in the blood, are used for diagnosis of APS. APS may also occur in the absence of any other related disease, where it is termed primary APSPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZXJ0b2xhY2Npbmk8L0F1dGhvcj48WWVhcj4yMDE0PC9Z
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ADDIN EN.CITE.DATA [143]. Catalase and glutathione peroxidase activities are decreased in monocytes and neutrophils of APS patients, perhaps because of the overproduction of H2O2 ADDIN EN.CITE <EndNote><Cite><Author>Ortona</Author><Year>2008</Year><RecNum>196</RecNum><DisplayText>[144]</DisplayText><record><rec-number>196</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511342257">196</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ortona, E.</author><author>Margutti, P.</author><author>Matarrese, P.</author><author>Franconi, F.</author><author>Malorni, W.</author></authors></contributors><auth-address>Department of Infectious diseases, Istituto Superiore di Sanita, Rome, Italy.</auth-address><titles><title>Redox state, cell death and autoimmune diseases: a gender perspective</title><secondary-title>Autoimmun Rev</secondary-title></titles><periodical><full-title>Autoimmun Rev</full-title><abbr-1>Autoimmunity reviews</abbr-1></periodical><pages>579-84</pages><volume>7</volume><number>7</number><keywords><keyword>*Apoptosis</keyword><keyword>Autoimmune Diseases/*etiology/immunology</keyword><keyword>Autoimmunity</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Oxidation-Reduction</keyword><keyword>Oxidative Stress</keyword><keyword>Reactive Oxygen Species/*metabolism</keyword><keyword>Sex Factors</keyword></keywords><dates><year>2008</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1568-9972 (Print)
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ADDIN EN.CITE.DATA [147]. Additionally, oxidative stress has been shown to be a risk factor for modifications to β2-glycoprotein-I that promote anti-phospholipid antibody:β2-glycoprotein-I interactions ADDIN EN.CITE <EndNote><Cite><Author>Passam</Author><Year>2011</Year><RecNum>205</RecNum><DisplayText>[148]</DisplayText><record><rec-number>205</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511342257">205</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Passam, F. H.</author><author>Giannakopoulos, B.</author><author>Mirarabshahi, P.</author><author>Krilis, S. A.</author></authors></contributors><auth-address>Department of Immunology, Allergy and Infectious Diseases, St George Hospital, University of New South Wales, Sydney, Australia.</auth-address><titles><title>Molecular pathophysiology of the antiphospholipid syndrome: the role of oxidative post-translational modification of beta 2 glycoprotein I</title><secondary-title>J Thromb Haemost</secondary-title></titles><periodical><full-title>J Thromb Haemost</full-title></periodical><pages>275-82</pages><volume>9 Suppl 1</volume><keywords><keyword>Antibodies, Antiphospholipid/blood</keyword><keyword>Antiphospholipid Syndrome/*genetics</keyword><keyword>Humans</keyword><keyword>Oxidation-Reduction</keyword><keyword>*Protein Processing, Post-Translational</keyword><keyword>beta 2-Glycoprotein I/*metabolism</keyword></keywords><dates><year>2011</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1538-7836 (Electronic)
1538-7836 (Linking)</isbn><accession-num>21781264</accession-num><urls><related-urls><url>;[148]. Anti-cardiolipin antibodies play a role in oxidative status, by inducing ●NO and O2- production, resulting in enhanced levels of plasma peroxynitrite ADDIN EN.CITE <EndNote><Cite><Author>Alves</Author><Year>2003</Year><RecNum>206</RecNum><DisplayText>[149]</DisplayText><record><rec-number>206</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511342257">206</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Alves, J. D.</author><author>Grima, B.</author></authors></contributors><auth-address>Autoimmune Disease Unit, Hospital Curry Cabral, Medicina 2, R. Beneficencia 8, 1069-166 Lisbon, Portugal. j.alves@ucl.ac.uk</auth-address><titles><title>Oxidative stress in systemic lupus erythematosus and antiphospholipid syndrome: a gateway to atherosclerosis</title><secondary-title>Curr Rheumatol Rep</secondary-title></titles><periodical><full-title>Curr Rheumatol Rep</full-title></periodical><pages>383-90</pages><volume>5</volume><number>5</number><keywords><keyword>Antibodies, Antiphospholipid/physiology</keyword><keyword>Antiphospholipid Syndrome/complications/*metabolism</keyword><keyword>Arteriosclerosis/*etiology/physiopathology</keyword><keyword>Humans</keyword><keyword>Lupus Erythematosus, Systemic/complications/*metabolism</keyword><keyword>*Oxidative Stress</keyword></keywords><dates><year>2003</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1523-3774 (Print)
1523-3774 (Linking)</isbn><accession-num>12967525</accession-num><urls><related-urls><url>;[149]. In humans, anti-phospholipid antibodies alone induce only minor activation of neutrophils, including oxidative burst at high antibody concentrations. However, in the presence of lipopolysaccharide, the activation threshold is markedly lower indicating a synergistic activation pathway of anti-phospholipid antibodies and toll-like receptor-4 in neutrophils. The toll-like receptor-2 ligand Pam3Cys is also synergistic with anti-phospholipid antibodies. This is in keeping with the fact that infections may be an additional factor potentiating the impact of anti-phospholipid antibodies in APSPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HbGFkaWdhdTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+
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ADDIN EN.CITE.DATA [146].Neutrophil-derived ROS may be a cause of miscarriage in APS. In this process, anti-phospholipid antibodies bind to trophoblasts, where they activate the complement cascade leading to the generation of C5a, attracting and activating neutrophils. C5a engages with its receptor C5aR, causing neutrophils to express tissue factor and protease activated receptor 2 (PAR2). Tissue factor forms a ternary complex with factor VIIa and factor Xa that activates PAR2, ROS production, trophoblast injury and ultimately fetal deathPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SZWRlY2hhPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48
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ADDIN EN.CITE.DATA [150-152]. Pravastatin, shown to prevent miscarriage in anti-phospholipid antibody-treated mice ADDIN EN.CITE <EndNote><Cite><Author>Girardi</Author><Year>2009</Year><RecNum>209</RecNum><DisplayText>[153]</DisplayText><record><rec-number>209</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511342257">209</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Girardi, G.</author></authors></contributors><auth-address>Hospital for Special Surgery, Department of Medicine, Weill Medical College of Cornell University, New York, NY, USA. girardig@hss.edu</auth-address><titles><title>Pravastatin prevents miscarriages in antiphospholipid antibody-treated mice</title><secondary-title>J Reprod Immunol</secondary-title></titles><periodical><full-title>J Reprod Immunol</full-title></periodical><pages>126-31</pages><volume>82</volume><number>2</number><keywords><keyword>Abortion, Habitual/*immunology/prevention & control</keyword><keyword>Animals</keyword><keyword>Antibodies, Antiphospholipid/administration & dosage/*immunology</keyword><keyword>Female</keyword><keyword>Injections, Intraperitoneal</keyword><keyword>Mice</keyword><keyword>Mice, Knockout</keyword><keyword>Mice, Transgenic</keyword><keyword>Neutrophil Activation/drug effects/genetics/immunology</keyword><keyword>Neutrophils/drug effects/immunology/*metabolism/pathology</keyword><keyword>Pravastatin/*administration & dosage</keyword><keyword>Pregnancy</keyword><keyword>Receptor, PAR-2/genetics/immunology/*metabolism</keyword><keyword>Simvastatin/administration & dosage</keyword><keyword>Thromboplastin/genetics/immunology/*metabolism</keyword></keywords><dates><year>2009</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1872-7603 (Electronic)
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ADDIN EN.CITE.DATA [151]. Vasculitis Vasculitis comprises a spectrum of disorders in which blood vessels are destroyed by inflammation. In anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, neutrophils are both the direct target of auto-antibodies and the main protagonist of vascular damage through the production of ROS. ANCA-associated vasculitis is classified as granulomatosis with polyangiitis (formerly Wegener’s granulomatosis), microscopic polyangiitis or eosinophilic granulomatosis (formerly Churg-Strauss syndrome). Auto-antibodies are produced against neutrophil granule proteins MPO or proteinase-3 (PR3), with anti-MPO ANCAs being most commonly associated with microscopic polyangiitis and anti-PR3 ANCAs being present in >90% of patients with granulomatosis with polyangiitisPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaGllYmxlbW9udDwvQXV0aG9yPjxZZWFyPjIwMTY8L1ll
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UaGllYmxlbW9udDwvQXV0aG9yPjxZZWFyPjIwMTY8L1ll
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dGU+AG==
ADDIN EN.CITE.DATA [9]. Anti-MPO ANCAs stimulate the production of ROS by unprimed, healthy control neutrophilsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YdTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA [156]. Activation of ROS by ANCAs is enhanced by the presence of high mobility group box-1 (HMGB1), an inflammatory protein which is elevated in the serum of vasculitis patients and which is associated with increased levels of neutrophil migration and vascular damage ADDIN EN.CITE <EndNote><Cite><Author>Wang</Author><Year>2017</Year><RecNum>47</RecNum><DisplayText>[157]</DisplayText><record><rec-number>47</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1507555028">47</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wang, C.</author><author>Chang, D. Y.</author><author>Chen, M.</author><author>Zhao, M. H.</author></authors></contributors><auth-address>Renal Division, Department of Medicine, Peking University First Hospital, Institute of Nephrology, Peking University, Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China.</auth-address><titles><title>HMGB1 contributes to glomerular endothelial cell injury in ANCA-associated vasculitis through enhancing endothelium-neutrophil interactions</title><secondary-title>J Cell Mol Med</secondary-title><alt-title>Journal of cellular and molecular medicine</alt-title></titles><periodical><full-title>J Cell Mol Med</full-title><abbr-1>Journal of cellular and molecular medicine</abbr-1></periodical><alt-periodical><full-title>J Cell Mol Med</full-title><abbr-1>Journal of cellular and molecular medicine</abbr-1></alt-periodical><pages>1351-1360</pages><volume>21</volume><number>7</number><edition>2017/02/10</edition><keywords><keyword>Anca</keyword><keyword>Hmgb1</keyword><keyword>glomerular endothelial cells</keyword><keyword>neutrophils</keyword></keywords><dates><year>2017</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>1582-4934 (Electronic)
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ADDIN EN.CITE.DATA [160]. Oxidised lipoproteins, associated with an elevated risk of atherosclerosis in vasculitis patients, are elevated in vasculitis serum and may form as a result of increased production of MPO-derived oxidants such as HOClPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TbG90PC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [162].Beh?ets disease is a form of vasculitis with multi-system involvement, including the eyes, mouth, genitals and brain. Although ANCAs are not present in patients with Beh?ets disease, activated neutrophils are found at sites of inflammation. Serum from Beh?ets patients stimulates production of both O2- and H2O2 species, and more specifically, serum from patients with active disease stimulates the production of higher levels of H2O2 than are produced in response to PMA in vitroPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QZXJhenppbzwvQXV0aG9yPjxZZWFyPjIwMTc8L1llYXI+
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ADDIN EN.CITE.DATA [163] which is present at significantly higher concentrations in Beh?ets patients compared to healthy controls and patients with SLE. Neutrophils from Beh?ets patients have also been shown to release high levels of ROS when stimulated with fMLP in vitroPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb3JrbWF6PC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48
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ADDIN EN.CITE.DATA [166,167]. As well as increased ROS production by neutrophils, vascular damage in Beh?ets disease may be mediated by dysregulation of the anti-oxidant system, including increased levels of superoxide dismutase and decreased levels of glutathione peroxidasePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Lb3NlPC9BdXRob3I+PFllYXI+MjAwMjwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA [167]. A separate study reported lower superoxide dismutase levels in Beh?ets disease, which was associated with lower serum and erythrocyte glutathione peroxidase, lower erythrocyte catalase, higher adenosine deaminase (a marker of T-cell and neutrophil activation) and increased lipid peroxidationPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FcmtpbGljPC9BdXRob3I+PFllYXI+MjAwMzwvWWVhcj48
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ADDIN EN.CITE.DATA [165]. Consumption of nitrate/nitrite by MPO, leading to depletion of these substrates for nitric oxide synthase reactions, decreases the production of nitric oxide (●NO), an essential regulator of smooth muscle contraction and vasodilationPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FaXNlcmljaDwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+
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ADDIN EN.CITE.DATA [170]. In addition, increased expression of cyclooxygenase-2 in Beh?ets neutrophils may contribute to increased vascular damage via the synthesis of pro-inflammatory prostaglandinsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NZWxpa29nbHU8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFy
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ADDIN EN.CITE.DATA [172]. PsoriasisPsoriasis is an auto-inflammatory disease of the skin characterised by the hyperproliferation of keratinocytes with increased cell turnover leading to the formation of plaques on the skin surface. Hallmark histological feature of psoriasis, such as the pustules of Kogoj and microabscesses of Munro, are formed by the accumulation of neutrophils within the dermis and epidermis respectively. Despite observed neutrophilia in plaques, psoriasis is thought to be a largely T cell driven disease, characterised by the high expression of type 1 cytokines in both plaques and serumPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaWFuaTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [174]. Whist cytokine-driven pathways are hugely important in the pathogenesis of psoriasis, there is considerable evidence for the additive role of a pro-oxidant:antioxidant imbalance ADDIN EN.CITE <EndNote><Cite><Author>Trouba</Author><Year>2004</Year><RecNum>155</RecNum><DisplayText>[175]</DisplayText><record><rec-number>155</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511340441">155</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Trouba, K.K.</author><author>Hamadeh, H.K.</author><author>Amin, R.P.</author><author>Germolec, D.R.</author></authors></contributors><titles><title>Oxidative stress and its role in skin disease</title><secondary-title>Antioxid Redox Signal</secondary-title></titles><periodical><full-title>Antioxid Redox Signal</full-title><abbr-1>Antioxidants & redox signaling</abbr-1></periodical><pages>665-673</pages><volume>4</volume><number>4</number><dates><year>2004</year></dates><urls></urls></record></Cite></EndNote>[175].As one of the most abundant cell types at active sites of psoriasis, the contribution of neutrophils to disease pathology is thought to be significant. Neutrophils isolated from patients with psoriasis degranulate both primary and secondary granules more readily than neutrophils from healthy controls. Furthermore, increased MPO and catalase activity is reported in psoriatic neutrophils ADDIN EN.CITE <EndNote><Cite><Author>Bloomfield</Author><Year>1983</Year><RecNum>150</RecNum><DisplayText>[176]</DisplayText><record><rec-number>150</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511340303">150</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bloomfield, F. J.</author><author>Young, M. M.</author></authors></contributors><titles><title>Enhanced release of inflammatory mediators from lithium-stimulated neutrophils in psoriasis</title><secondary-title>Br J Dermatol</secondary-title><alt-title>The British journal of dermatology</alt-title></titles><periodical><full-title>Br J Dermatol</full-title><abbr-1>The British journal of dermatology</abbr-1></periodical><alt-periodical><full-title>Br J Dermatol</full-title><abbr-1>The British journal of dermatology</abbr-1></alt-periodical><pages>9-13</pages><volume>109</volume><number>1</number><edition>1983/07/01</edition><keywords><keyword>Catalase/blood</keyword><keyword>Cytoplasmic Granules/physiology</keyword><keyword>Glucuronidase/secretion</keyword><keyword>Humans</keyword><keyword>Lithium/*pharmacology</keyword><keyword>Neutrophils/drug effects/enzymology/*physiology</keyword><keyword>Peroxidase/blood</keyword><keyword>Psoriasis/*blood/enzymology</keyword><keyword>Transcobalamins/secretion</keyword></keywords><dates><year>1983</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0007-0963 (Print)
0007-0963 (Linking)</isbn><accession-num>6305386</accession-num><work-type>Research Support, Non-U.S. Gov't</work-type><urls><related-urls><url>;[176]. It has also been reported that psoriatic neutrophils exhibit enhanced NOX2 activity and that they can produce more ROS than healthy neutrophils, even in the absence of autologous serum ADDIN EN.CITE <EndNote><Cite><Author>Bloomfield</Author><Year>1988</Year><RecNum>151</RecNum><DisplayText>[177]</DisplayText><record><rec-number>151</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511340303">151</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bloomfield, F. J.</author><author>Young, M. M.</author></authors></contributors><auth-address>Department of Clinical Medicine, St. James Hospital, Dublin, Ireland.</auth-address><titles><title>Enhanced chemiluminescence production by phagocytosing neutrophils in psoriasis</title><secondary-title>Inflammation</secondary-title><alt-title>Inflammation</alt-title></titles><periodical><full-title>Inflammation</full-title><abbr-1>Inflammation</abbr-1></periodical><alt-periodical><full-title>Inflammation</full-title><abbr-1>Inflammation</abbr-1></alt-periodical><pages>153-9</pages><volume>12</volume><number>2</number><edition>1988/04/01</edition><keywords><keyword>Female</keyword><keyword>Humans</keyword><keyword>Luminescent Measurements</keyword><keyword>Male</keyword><keyword>Neutrophils/*immunology</keyword><keyword>*Phagocytosis</keyword><keyword>Psoriasis/*immunology</keyword><keyword>Zymosan</keyword></keywords><dates><year>1988</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0360-3997 (Print)
0360-3997 (Linking)</isbn><accession-num>3391684</accession-num><work-type>Research Support, Non-U.S. Gov't</work-type><urls><related-urls><url>;[177]. Whilst this indicates that psoriatic neutrophils have a constitutively enhanced capacity to produce ROS, it does not mean that psoriatic sera does not contribute to increased neutrophil activation, as healthy neutrophils demonstrate increased O2- generation when incubated in serum from psoriasis patients ADDIN EN.CITE <EndNote><Cite><Author>Sedgwick</Author><Year>1981</Year><RecNum>154</RecNum><DisplayText>[178]</DisplayText><record><rec-number>154</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511340303">154</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sedgwick, J. B.</author><author>Bergstresser, P. R.</author><author>Hurd, E. R.</author></authors></contributors><titles><title>Increased superoxide generation by normal granulocytes incubated in sera from patients with psoriasis</title><secondary-title>J Invest Dermatol</secondary-title><alt-title>The Journal of investigative dermatology</alt-title></titles><periodical><full-title>J Invest Dermatol</full-title><abbr-1>The Journal of investigative dermatology</abbr-1></periodical><alt-periodical><full-title>J Invest Dermatol</full-title><abbr-1>The Journal of investigative dermatology</abbr-1></alt-periodical><pages>158-63</pages><volume>76</volume><number>3</number><edition>1981/03/01</edition><keywords><keyword>Ceruloplasmin/analysis</keyword><keyword>Complement Activation</keyword><keyword>Complement System Proteins/analysis</keyword><keyword>Cytochrome c Group/metabolism</keyword><keyword>Female</keyword><keyword>Granulocytes/*metabolism</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Neutrophils/metabolism</keyword><keyword>Oxygen/*biosynthesis</keyword><keyword>Psoriasis/*blood/etiology</keyword><keyword>Superoxides/*biosynthesis</keyword><keyword>Zymosan/pharmacology</keyword></keywords><dates><year>1981</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0022-202X (Print)
0022-202X (Linking)</isbn><accession-num>6263980</accession-num><work-type>Research Support, U.S. Gov't, P.H.S.</work-type><urls><related-urls><url>;[178]. As well as increased ROS generation, neutrophils from patients with psoriasis have been reported to have lower activity of key antioxidant enzymes, superoxide dismutase and glutathione peroxidase,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Eb2dhbjwvQXV0aG9yPjxZZWFyPjE5ODk8L1llYXI+PFJl
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ADDIN EN.CITE.DATA [179,180], and decreased activity of glutathione peroxidase also correlates with increase disease s have been observed in psoriatic lesions and neutrophils isolated from the blood of psoriasis patients more readily undergo the ROS-driven process of NETosis than neutrophils from healthy controls. Interestingly, in these individuals spontaneous NETosis correlates with disease severity. As has been shown in the case of neutrophil ROS production, this phenomenon is not a primary psoriatic neutrophil defect, as psoriatic serum also induces NETosis in healthy neutrophils ADDIN EN.CITE <EndNote><Cite><Author>Hu</Author><Year>2016</Year><RecNum>158</RecNum><DisplayText>[181]</DisplayText><record><rec-number>158</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511340709">158</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hu, S. C.</author><author>Yu, H. S.</author><author>Yen, F. L.</author><author>Lin, C. L.</author><author>Chen, G. S.</author><author>Lan, C. C.</author></authors></contributors><auth-address>Department of Dermatology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.
National Institute of Environmental Health Sciences, National Health Research Institutes, Taipei, Taiwan.
Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
Department of Dermatology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan.</auth-address><titles><title>Neutrophil extracellular trap formation is increased in psoriasis and induces human beta-defensin-2 production in epidermal keratinocytes</title><secondary-title>Sci Rep</secondary-title><alt-title>Scientific reports</alt-title></titles><periodical><full-title>Sci Rep</full-title><abbr-1>Scientific reports</abbr-1></periodical><alt-periodical><full-title>Sci Rep</full-title><abbr-1>Scientific reports</abbr-1></alt-periodical><pages>31119</pages><volume>6</volume><edition>2016/08/06</edition><dates><year>2016</year><pub-dates><date>Aug 05</date></pub-dates></dates><isbn>2045-2322 (Electronic)
2045-2322 (Linking)</isbn><accession-num>27493143</accession-num><urls><related-urls><url>;[181]. Interestingly, this NET formation is likely to be ROS dependent as it is blocked by dimethyl fumurate in a ROS-dependent manner ADDIN EN.CITE <EndNote><Cite><Author>Hoffmann</Author><Year>2017</Year><RecNum>171</RecNum><DisplayText>[182]</DisplayText><record><rec-number>171</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511341562">171</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hoffmann, J. H. O.</author><author>Schaekel, K.</author><author>Hartl, D.</author><author>Enk, A. H.</author><author>Hadaschik, E. N.</author></authors></contributors><auth-address>Department of Dermatology, University of Heidelberg, Heidelberg, Germany.
University children's hospital, University of Tubingen, Tubingen, Germany and Roche Pharma Research& Early Development (pRED), Immunology, Inflammation and Infectious Diseases (I3) Discovery and Translational Area, Basel, Switzerland.</auth-address><titles><title>Dimethyl fumarate modulates neutrophil extracellular trap formation in a glutathione and superoxide-dependent manner</title><secondary-title>Br J Dermatol</secondary-title><alt-title>The British journal of dermatology</alt-title></titles><periodical><full-title>Br J Dermatol</full-title><abbr-1>The British journal of dermatology</abbr-1></periodical><alt-periodical><full-title>Br J Dermatol</full-title><abbr-1>The British journal of dermatology</abbr-1></alt-periodical><edition>2017/07/25</edition><dates><year>2017</year><pub-dates><date>Jul 22</date></pub-dates></dates><isbn>1365-2133 (Electronic)
0007-0963 (Linking)</isbn><accession-num>28733990</accession-num><urls><related-urls><url>;[182].The effect of the local tissue environment on neutrophil ROS generation in psoriasis has recently been further delineated. It has been demonstrated that neutrophils in psoriatic lesions have an increased capacity for activation, mediated by both keratinocytes and T cells. Psoriatic keratinocytes produce significantly more TNF-α, monocyte chemoattractant protein 1 (MCP-1), IL-8 and GM-CSF than keratinocytes from healthy individualsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJ0aW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [184]. There have been two waves of interest in neutrophil involvement in psoriasis pathogenesis. The first wave, between the late 1970s and early 1990s focussed on neutrophil adhesion, phagocytosis, degranulation and ROS generation. With the discovery of T cell involvement, particularly Th17 cells, interest in psoriatic neutrophils waned ADDIN EN.CITE <EndNote><Cite><Author>Schon</Author><Year>2017</Year><RecNum>164</RecNum><DisplayText>[185]</DisplayText><record><rec-number>164</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511340709">164</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schon, M. P.</author><author>Broekaert, S. M.</author><author>Erpenbeck, L.</author></authors></contributors><auth-address>Department of Dermatology, Venereology and Allergolosgy, University Medical Center Gottingen, Gottingen, Germany.</auth-address><titles><title>Sexy again: the renaissance of neutrophils in psoriasis</title><secondary-title>Exp Dermatol</secondary-title><alt-title>Experimental dermatology</alt-title></titles><periodical><full-title>Exp Dermatol</full-title><abbr-1>Experimental dermatology</abbr-1></periodical><alt-periodical><full-title>Exp Dermatol</full-title><abbr-1>Experimental dermatology</abbr-1></alt-periodical><pages>305-311</pages><volume>26</volume><number>4</number><edition>2016/05/20</edition><keywords><keyword>comorbidity</keyword><keyword>leukocyte recruitment</keyword><keyword>neutrophil extracellular trap</keyword><keyword>neutrophilic granulocytes</keyword><keyword>psoriasis</keyword></keywords><dates><year>2017</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1600-0625 (Electronic)
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ADDIN EN.CITE.DATA [188,189], it has led to a renewed interest in neutrophil involvement in psoriasis, and though welcome, it may be poorly directed. It would be wholly more interesting and logical to concentrate attention on the involvement of neutrophil-derived ROS, and on VEGF expression by keratinocytes. Both healthy and psoriatic keratinocytes produce high concentrations of ROS; however, unlike cytokines, VEGF is not up-regulated in keratinocytes during co-incubation with IL-2-treated T cells and so increased VEGF expression must be mediated by some other cell typePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJ0aW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA [190] and it is therefore not inconceivable to suggest that psoriatic neutrophils, which have low glutathione peroxidase activity ADDIN EN.CITE <EndNote><Cite><Author>Seifert</Author><Year>2007</Year><RecNum>170</RecNum><DisplayText>[180]</DisplayText><record><rec-number>170</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511341221">170</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Seifert, O.</author><author>Holmberg, J.</author><author>Linnarsson, B. M.</author></authors></contributors><titles><title>Decreased activity of neutrophil glutathione peroxidase in chronic plaque-type psoriasis</title><secondary-title>J Am Acad Dermatol</secondary-title><alt-title>Journal of the American Academy of Dermatology</alt-title></titles><periodical><full-title>J Am Acad Dermatol</full-title><abbr-1>Journal of the American Academy of Dermatology</abbr-1></periodical><alt-periodical><full-title>J Am Acad Dermatol</full-title><abbr-1>Journal of the American Academy of Dermatology</abbr-1></alt-periodical><pages>528-9</pages><volume>57</volume><number>3</number><edition>2007/08/21</edition><keywords><keyword>Adult</keyword><keyword>Aged</keyword><keyword>Chronic Disease</keyword><keyword>Female</keyword><keyword>Glutathione Peroxidase/*metabolism</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Neutrophils/*enzymology</keyword><keyword>Psoriasis/*enzymology/*pathology</keyword><keyword>Severity of Illness Index</keyword></keywords><dates><year>2007</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1097-6787 (Electronic)
0190-9622 (Linking)</isbn><accession-num>17707156</accession-num><work-type>Letter
Research Support, Non-U.S. Gov't</work-type><urls><related-urls><url>;[180], low superoxide dismutase activity ADDIN EN.CITE <EndNote><Cite><Author>Dogan</Author><Year>1989</Year><RecNum>157</RecNum><DisplayText>[179]</DisplayText><record><rec-number>157</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511340709">157</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dogan, P.</author><author>Soyuer, U.</author><author>Tanrikulu, G.</author></authors></contributors><auth-address>Department of Biochemistry, Faculty of Medicine, Erciyes University, Kayseri, Turkey.</auth-address><titles><title>Superoxide dismutase and myeloperoxidase activity in polymorphonuclear leukocytes, and serum ceruloplasmin and copper levels, in psoriasis</title><secondary-title>Br J Dermatol</secondary-title><alt-title>The British journal of dermatology</alt-title></titles><periodical><full-title>Br J Dermatol</full-title><abbr-1>The British journal of dermatology</abbr-1></periodical><alt-periodical><full-title>Br J Dermatol</full-title><abbr-1>The British journal of dermatology</abbr-1></alt-periodical><pages>239-44</pages><volume>120</volume><number>2</number><edition>1989/02/01</edition><keywords><keyword>Adolescent</keyword><keyword>Adult</keyword><keyword>Ceruloplasmin/*blood</keyword><keyword>Copper/*blood</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Middle Aged</keyword><keyword>Neutrophils/enzymology</keyword><keyword>Peroxidase/*blood</keyword><keyword>Psoriasis/*blood/enzymology</keyword><keyword>Superoxide Dismutase/*blood</keyword></keywords><dates><year>1989</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0007-0963 (Print)
0007-0963 (Linking)</isbn><accession-num>2538138</accession-num><work-type>Research Support, Non-U.S. Gov't</work-type><urls><related-urls><url>;[179], greater NOX2 activity and oxidative bursts ADDIN EN.CITE <EndNote><Cite><Author>Bloomfield</Author><Year>1988</Year><RecNum>151</RecNum><DisplayText>[177]</DisplayText><record><rec-number>151</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511340303">151</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bloomfield, F. J.</author><author>Young, M. M.</author></authors></contributors><auth-address>Department of Clinical Medicine, St. James Hospital, Dublin, Ireland.</auth-address><titles><title>Enhanced chemiluminescence production by phagocytosing neutrophils in psoriasis</title><secondary-title>Inflammation</secondary-title><alt-title>Inflammation</alt-title></titles><periodical><full-title>Inflammation</full-title><abbr-1>Inflammation</abbr-1></periodical><alt-periodical><full-title>Inflammation</full-title><abbr-1>Inflammation</abbr-1></alt-periodical><pages>153-9</pages><volume>12</volume><number>2</number><edition>1988/04/01</edition><keywords><keyword>Female</keyword><keyword>Humans</keyword><keyword>Luminescent Measurements</keyword><keyword>Male</keyword><keyword>Neutrophils/*immunology</keyword><keyword>*Phagocytosis</keyword><keyword>Psoriasis/*immunology</keyword><keyword>Zymosan</keyword></keywords><dates><year>1988</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>0360-3997 (Print)
0360-3997 (Linking)</isbn><accession-num>3391684</accession-num><work-type>Research Support, Non-U.S. Gov't</work-type><urls><related-urls><url>;[177], and which degranulate more readily ADDIN EN.CITE <EndNote><Cite><Author>Bloomfield</Author><Year>1983</Year><RecNum>150</RecNum><DisplayText>[176]</DisplayText><record><rec-number>150</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1511340303">150</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bloomfield, F. J.</author><author>Young, M. M.</author></authors></contributors><titles><title>Enhanced release of inflammatory mediators from lithium-stimulated neutrophils in psoriasis</title><secondary-title>Br J Dermatol</secondary-title><alt-title>The British journal of dermatology</alt-title></titles><periodical><full-title>Br J Dermatol</full-title><abbr-1>The British journal of dermatology</abbr-1></periodical><alt-periodical><full-title>Br J Dermatol</full-title><abbr-1>The British journal of dermatology</abbr-1></alt-periodical><pages>9-13</pages><volume>109</volume><number>1</number><edition>1983/07/01</edition><keywords><keyword>Catalase/blood</keyword><keyword>Cytoplasmic Granules/physiology</keyword><keyword>Glucuronidase/secretion</keyword><keyword>Humans</keyword><keyword>Lithium/*pharmacology</keyword><keyword>Neutrophils/drug effects/enzymology/*physiology</keyword><keyword>Peroxidase/blood</keyword><keyword>Psoriasis/*blood/enzymology</keyword><keyword>Transcobalamins/secretion</keyword></keywords><dates><year>1983</year><pub-dates><date>Jul</date></pub-dates></dates><isbn>0007-0963 (Print)
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ADDIN EN.CITE.DATA [166]. However the precise role of neutrophils in the pathogenesis of multiple sclerosis?is still under question; whilst peripheral blood neutrophils are activated in multiple sclerosis they are not found within the central nervous system, and neutrophil products (such as NETs) are not found within cerebral spinal fluid. A potential role for neutrophil proteases such as matrix metalloproteinases in opening the blood:brain barrier has been proposed ADDIN EN.CITE <EndNote><Cite><Author>Pierson</Author><Year>2016</Year><RecNum>57</RecNum><DisplayText>[194]</DisplayText><record><rec-number>57</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1508244838">57</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pierson, E. R.</author><author>Wagner, C. A.</author><author>Goverman, J. M.</author></authors></contributors><auth-address>Department of Immunology, University of Washington, Box 358059, 750 Republican St., Seattle, WA 98109-8509, USA.
Department of Immunology, University of Washington, Box 358059, 750 Republican St., Seattle, WA 98109-8509, USA. Electronic address: goverman@uw.edu.</auth-address><titles><title>The contribution of neutrophils to CNS autoimmunity</title><secondary-title>Clin Immunol</secondary-title><alt-title>Clinical immunology</alt-title></titles><periodical><full-title>Clin Immunol</full-title><abbr-1>Clinical immunology</abbr-1></periodical><alt-periodical><full-title>Clin Immunol</full-title><abbr-1>Clinical immunology</abbr-1></alt-periodical><edition>2016/07/06</edition><keywords><keyword>Cxcr2</keyword><keyword>Eae</keyword><keyword>Il-17</keyword><keyword>Ms</keyword><keyword>Neutrophils</keyword></keywords><dates><year>2016</year><pub-dates><date>Jul 01</date></pub-dates></dates><isbn>1521-7035 (Electronic)
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ADDIN EN.CITE.DATA [195], with MPO-positive neutrophil numbers remaining elevated in the brain during disease remission but increasing further during relapse. However, in humans the main source of MPO and ROS within brain lesions is believed to be macrophages ADDIN EN.CITE <EndNote><Cite><Author>Gray</Author><Year>2008</Year><RecNum>51</RecNum><DisplayText>[196]</DisplayText><record><rec-number>51</rec-number><foreign-keys><key app="EN" db-id="955ffd5x7vt2wje5ea0vxfxurzpex9zptava" timestamp="1508244838">51</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gray, E.</author><author>Thomas, T. L.</author><author>Betmouni, S.</author><author>Scolding, N.</author><author>Love, S.</author></authors></contributors><auth-address>MS Laboratories, Burden Centre, University of Bristol Institute of Clinical Neurosciences, Frenchay Hospital, Bristol BS16 1JB, United Kingdom.</auth-address><titles><title>Elevated myeloperoxidase activity in white matter in multiple sclerosis</title><secondary-title>Neurosci Lett</secondary-title><alt-title>Neuroscience letters</alt-title></titles><periodical><full-title>Neurosci Lett</full-title><abbr-1>Neuroscience letters</abbr-1></periodical><alt-periodical><full-title>Neurosci Lett</full-title><abbr-1>Neuroscience letters</abbr-1></alt-periodical><pages>195-8</pages><volume>444</volume><number>2</number><edition>2008/08/30</edition><keywords><keyword>Brain/*enzymology/pathology</keyword><keyword>Fluorescent Antibody Technique</keyword><keyword>Humans</keyword><keyword>Multiple Sclerosis/*enzymology/pathology</keyword><keyword>Peroxidase/*metabolism</keyword></keywords><dates><year>2008</year><pub-dates><date>Oct 24</date></pub-dates></dates><isbn>0304-3940 (Print)
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ADDIN EN.CITE.DATA [91]. Closing remarksThis review of recent literature clearly demonstrates that neutrophils are primed to release higher levels of ROS in a number of auto-immune disease settings, and that damage mediated to host tissue by neutrophil-derived oxidants (both primary and secondary) contributes to disease pathology (summarised in Figure 2). However, there is insufficient detail in the literature about the involvement, relevance, and concentrations of specific ROS species in vivo in auto-immune diseases. Many studies measure the ability of ex vivo patient neutrophils to produce ROS in response to non-physiological stimuli (e.g. PMA) or pathological agonists such as autologous serum or auto-antibodies, with little regard for the species of ROS being produced. As this review and the work of others clearly shows, the production of different ROS species is highly relevant both in terms of the cellular microenvironment, disease pathology and the manifestation of oxidative damage at the cellular and tissue level. As technologies and techniques for the study of redox reactions become more sophisticated, it is important to revisit some of the experiments reviewed here, to understand the role of specific neutrophil-derived oxidants in finer detail.AcknowledgementsNoneFundingThis work was supported by Arthritis Research UK [Grant No 21430], the Wellcome Trust [Grant No 200605/Z/16/Z], Novartis [Grant No CAIN457F2301T] and Liverpool Health Partners.References ADDIN EN.REFLIST 1. Wright HL, Moots RJ, Bucknall RC, Edwards SW (2010) Neutrophil function in inflammation and inflammatory diseases. Rheumatology (Oxford) 49: 1618-1631.2. Koh TJ, DiPietro LA (2011) Inflammation and wound healing: the role of the macrophage. Expert Rev Mol Med 13: e23.3. 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(2012) Neutrophils in multiple sclerosis are characterized by a primed phenotype. J Neuroimmunol 242: 60-71.193. Tillack K, Naegele M, Haueis C, Schippling S, Wandinger KP, et al. (2013) Gender differences in circulating levels of neutrophil extracellular traps in serum of multiple sclerosis patients. J Neuroimmunol 261: 108-119.194. Pierson ER, Wagner CA, Goverman JM (2016) The contribution of neutrophils to CNS autoimmunity. Clin Immunol. pii: S1521-6616(16)30143-7. doi: 10.1016/j.clim.2016.06.017.195. Pulli B, Bure L, Wojtkiewicz GR, Iwamoto Y, Ali M, et al. (2015) Multiple sclerosis: myeloperoxidase immunoradiology improves detection of acute and chronic disease in experimental model. Radiology 275: 480-489.196. Gray E, Thomas TL, Betmouni S, Scolding N, Love S (2008) Elevated myeloperoxidase activity in white matter in multiple sclerosis. Neurosci Lett 444: 195-198.FiguresFigure 1. Production of reactive oxygen species (ROS) within the neutrophil phagosome. Priming of a neutrophil, e.g. by a cytokine, triggers mobilisation of cytoplasmic phox and Rac proteins and membrane-expressed cytochrome b558 (Cyt b) to assemble the NADPH oxidase (NOX2) at the phagosomal membrane. Reduction of oxygen in the presence of NADPH by NOX2 produces O2- within the phagosome. This in turn dismutates enzymatically (via superoxide dismutase) or spontaneously into H2O2. Priming also stimulates fusion of neutrophil granules with the phagosome leading to release of myeloperoxidase (MPO) which produces secondary HOCl from reactions with H2O2.Figure 2. Neutrophil-derived oxidants in the pathogenesis of auto-immune disease. Production of ROS including O2-, H2O2 and HOCl, both intracelullarly and extracellulary, regulates a myriad of neutrophil functions, as well as inducing oxidative damage at the molecular, cellular and tissue level which contributes to disease pathogenesis and damage to host tissue. ARE, antioxidant response element; NET, neutrophil extracelllular trap; NOS, nitric oxide synthase; TF, transcription factor. ................
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