Research Explorer | The University of Manchester



The CD44-mediated uptake of hyaluronic acid-based carriers in macrophagesJulio M. Rios de la Rosa, Annalisa Tirella, Arianna Gennari, Ian J. Stratford and Nicola Tirelli*Mr. J.M. de la Rosa, Dr. A. Tirella, Dr. A. Gennari, Prof. I.J. Stratford, Prof. N. Tirelli*NorthWest Centre for Advanced Drug Delivery (NoWCADD), Division of Pharmacy and Optometry, School of Health Sciences, University of Manchester, Manchester, M13 9PT (United Kingdom)E-mail: nicola.tirelli@manchester.ac.ukAbstractCD44 is a potentially rewarding target in cancer therapy, whose mechanisms of ligand binding and internalization are still poorly understood. Here, we draft quantitative relations between the expression of CD44 in differently polarized macrophages (M0, M1 and M2-polarized THP-1 human macrophages) and the uptake of hyaluronic acid (HA)-based materials potentially usable for CD44 targeting.Employing a robust method for macrophage /polarization, which sequentially uses differentiating and polarizing factors, we show that CD44 expression depends on polarization (M1>M0M2. We also show that THP-1 M2 express CD44v6, suggesting their suitability to model tumour-associated macrophages.In the uptake of HA, both as a soluble polymer and in the form of (siRNA-loaded) nanoparticles, we show on one hand a positive correlation between CD44 expression and cell binding, and on the other a clearly negative one with cellular internalization. Counterintuitively, it appears that a higher presence of CD44 (M1) allows a more efficient capture of HA materials, but a lower expression (M2) is conducive to better internalization. Although possibly cell-specific, this unexpected relationship indicates that the common paradigm “higher CD44 expression = better targetability” is too simplistic; mechanistic details of both receptor presentation and association still need to be elucidated for a predictable targeting behaviour.Keywords: CD44; nanoparticles; endocytosis; hyaluronan1. IntroductionThe involvement of CD44 in tumorigenesis, acquisition of metastatic phenotype, and putatively as a cancer stem cell (CSC) marker PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxsaWFtczwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+

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ADDIN EN.CITE.DATA [1] has made this receptor an interesting target in drug delivery PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Kb3JkYW48L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [2]. Currently, two families of agents are used to target it: A) hyaluronic acid (HA)-based materials. HA is the most common natural ligand for CD44 ADDIN EN.CITE <EndNote><Cite><Author>Aruffo</Author><Year>1990</Year><RecNum>5</RecNum><DisplayText><style face="superscript">[3]</style></DisplayText><record><rec-number>5</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1465304180">5</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Aruffo, A.</author><author>Stamenkovic, I.</author><author>Melnick, M.</author><author>Underhill, C. B.</author><author>Seed, B.</author></authors></contributors><auth-address>Aruffo, A&#xD;Harvard Univ,Sch Med,Dept Genet,Boston,Ma 02115, USA&#xD;Harvard Univ,Sch Med,Dept Genet,Boston,Ma 02115, USA&#xD;Harvard Univ,Sch Med,Dept Pathol,Boston,Ma 02115&#xD;Massachusetts Gen Hosp,Dept Molec Biol,Boston,Ma 02114&#xD;Georgetown Univ,Med Ctr,Dept Anat &amp; Cell Biol,Washington,Dc 20007</auth-address><titles><title>CD44 Is the principal cell-surface receptor for hyaluronate</title><secondary-title>Cell</secondary-title><alt-title>Cell</alt-title></titles><periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></periodical><alt-periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></alt-periodical><pages>1303-1313</pages><volume>61</volume><number>7</number><dates><year>1990</year><pub-dates><date>Jun 29</date></pub-dates></dates><isbn>0092-8674</isbn><accession-num>ISI:A1990DM15600018</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://A1990DM15600018</url></related-urls></urls><electronic-resource-num>Doi 10.1016/0092-8674(90)90694-A</electronic-resource-num><language>English</language></record></Cite></EndNote>[3] and has been used either directly as a carrierPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BdXplbm5lPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48

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ADDIN EN.CITE.DATA [8]. The downsides of this approach are the competition with the host own HA, and the moderate (from a few to hundreds of ?M ADDIN EN.CITE <EndNote><Cite><Author>Skelton</Author><Year>1998</Year><RecNum>71</RecNum><DisplayText><style face="superscript">[9]</style></DisplayText><record><rec-number>71</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1470636136">71</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Skelton, T. P.</author><author>Zeng, C. X.</author><author>Nocks, A.</author><author>Stamenkovic, I.</author></authors></contributors><auth-address>Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02129 USA. Massachusetts Gen Hosp, Charlestown Navy Yard, Boston, MA 02129 USA.&#xD;Stamenkovic, I (reprint author), Harvard Univ, Sch Med, Dept Pathol, Charlestown Navy Yard,149 13th St, Boston, MA 02129 USA.</auth-address><titles><title>Glycosylation provides both stimulatory and inhibitory effects on cell surface and soluble CD44 binding to hyaluronan</title><secondary-title>Journal of Cell Biology</secondary-title><alt-title>J. Cell Biol.</alt-title></titles><periodical><full-title>Journal of Cell Biology</full-title><abbr-1>J Cell Biol</abbr-1></periodical><pages>431-446</pages><volume>140</volume><number>2</number><keywords><keyword>affinity capillary electrophoresis</keyword><keyword>homing receptor cd44</keyword><keyword>hamster ovary</keyword><keyword>cells</keyword><keyword>spliced exons</keyword><keyword>human-breast</keyword><keyword>t-cells</keyword><keyword>expression</keyword><keyword>adhesion</keyword><keyword>protein</keyword><keyword>recognition</keyword><keyword>Cell Biology</keyword></keywords><dates><year>1998</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0021-9525</isbn><accession-num>WOS:000071798000018</accession-num><work-type>Article</work-type><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000071798000018</url></related-urls></urls><electronic-resource-num>10.1083/jcb.140.2.431</electronic-resource-num><language>English</language></record></Cite></EndNote>[9]) affinity of CD44 for HA, which is also affected by a number of complicating factors, e.g. post-translational modifications ADDIN EN.CITE <EndNote><Cite><Author>Skelton</Author><Year>1998</Year><RecNum>71</RecNum><DisplayText><style face="superscript">[9]</style></DisplayText><record><rec-number>71</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1470636136">71</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Skelton, T. P.</author><author>Zeng, C. X.</author><author>Nocks, A.</author><author>Stamenkovic, I.</author></authors></contributors><auth-address>Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02129 USA. Massachusetts Gen Hosp, Charlestown Navy Yard, Boston, MA 02129 USA.&#xD;Stamenkovic, I (reprint author), Harvard Univ, Sch Med, Dept Pathol, Charlestown Navy Yard,149 13th St, Boston, MA 02129 USA.</auth-address><titles><title>Glycosylation provides both stimulatory and inhibitory effects on cell surface and soluble CD44 binding to hyaluronan</title><secondary-title>Journal of Cell Biology</secondary-title><alt-title>J. Cell Biol.</alt-title></titles><periodical><full-title>Journal of Cell Biology</full-title><abbr-1>J Cell Biol</abbr-1></periodical><pages>431-446</pages><volume>140</volume><number>2</number><keywords><keyword>affinity capillary electrophoresis</keyword><keyword>homing receptor cd44</keyword><keyword>hamster ovary</keyword><keyword>cells</keyword><keyword>spliced exons</keyword><keyword>human-breast</keyword><keyword>t-cells</keyword><keyword>expression</keyword><keyword>adhesion</keyword><keyword>protein</keyword><keyword>recognition</keyword><keyword>Cell Biology</keyword></keywords><dates><year>1998</year><pub-dates><date>Jan</date></pub-dates></dates><isbn>0021-9525</isbn><accession-num>WOS:000071798000018</accession-num><work-type>Article</work-type><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000071798000018</url></related-urls></urls><electronic-resource-num>10.1083/jcb.140.2.431</electronic-resource-num><language>English</language></record></Cite></EndNote>[9] and in particular N-glycosylationPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5FbmdsaXNoPC9BdXRob3I+PFllYXI+MTk5ODwvWWVhcj48

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ADDIN EN.CITE.DATA [12], the presence of CD44 in a soluble form ADDIN EN.CITE <EndNote><Cite><Author>Cichy</Author><Year>2003</Year><RecNum>74</RecNum><DisplayText><style face="superscript">[13]</style></DisplayText><record><rec-number>74</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1470636706">74</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Cichy, J.</author><author>Pure, E.</author></authors></contributors><auth-address>Jagiellonian Univ, Fac Biotechnol, PL-30387 Krakow, Poland. Wistar Inst Anat &amp; Biol, Philadelphia, PA 19104 USA. Ludwig Inst Canc Res, New York, NY 10158 USA.&#xD;Cichy, J (reprint author), Jagiellonian Univ, Fac Biotechnol, Ul Gronostajowa 7, PL-30387 Krakow, Poland.</auth-address><titles><title>The liberation of CD44</title><secondary-title>Journal of Cell Biology</secondary-title><alt-title>J. Cell Biol.</alt-title></titles><periodical><full-title>Journal of Cell Biology</full-title><abbr-1>J Cell Biol</abbr-1></periodical><pages>839-843</pages><volume>161</volume><number>5</number><keywords><keyword>CD44</keyword><keyword>proteolytic processing</keyword><keyword>extracellular matrix</keyword><keyword>cell adhesion</keyword><keyword>presenilin</keyword><keyword>mammary-carcinoma cells</keyword><keyword>soluble cd44</keyword><keyword>intramembrane proteolysis</keyword><keyword>intracellular domain</keyword><keyword>hyaluronan-binding</keyword><keyword>peripheral-blood</keyword><keyword>tumor</keyword><keyword>invasion</keyword><keyword>cleavage</keyword><keyword>mice</keyword><keyword>matrix-metalloproteinase-9</keyword><keyword>Cell Biology</keyword></keywords><dates><year>2003</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0021-9525</isbn><accession-num>WOS:000183504700001</accession-num><work-type>Review</work-type><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000183504700001</url></related-urls></urls><electronic-resource-num>10.1083/jcb.200302098</electronic-resource-num><language>English</language></record></Cite></EndNote>[13] and also the variable degree of clustering of this receptor.B) monoclonal antibodies. Their CD44 ligation contributes to both targeting and therapeutic effects ADDIN EN.CITE <EndNote><Cite><Author>Liu</Author><Year>2006</Year><RecNum>61</RecNum><DisplayText><style face="superscript">[14]</style></DisplayText><record><rec-number>61</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1470401572">61</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Liu, J. N.</author><author>Jiang, G. S.</author></authors></contributors><auth-address>[Liu, Jianing; Jiang, Guosheng] Shandong Acad Med Sci, Inst Basic Med, Dept Hematol Oncol, Jinan 250062, Shandong, Peoples R China.&#xD;Jiang, GS (reprint author), Shandong Acad Med Sci, Inst Basic Med, Dept Hematol Oncol, Jingshi Rd 89, Jinan 250062, Shandong, Peoples R China.&#xD;Jianggsh@</auth-address><titles><title>CD44 and Hematologic Malignancies</title><secondary-title>Cellular &amp; Molecular Immunology</secondary-title><alt-title>Cell. Mol. Immunol.</alt-title></titles><periodical><full-title>Cellular &amp; Molecular Immunology</full-title><abbr-1>Cell. Mol. Immunol.</abbr-1></periodical><alt-periodical><full-title>Cellular &amp; Molecular Immunology</full-title><abbr-1>Cell. Mol. Immunol.</abbr-1></alt-periodical><pages>359-365</pages><volume>3</volume><number>5</number><keywords><keyword>CD44</keyword><keyword>hematological malignancy</keyword><keyword>prognosis</keyword><keyword>therapy</keyword><keyword>Immunology</keyword></keywords><dates><year>2006</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1672-7681</isbn><accession-num>WOS:000208926600005</accession-num><work-type>Review</work-type><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000208926600005</url></related-urls></urls><language>English</language></record></Cite></EndNote>[14], an effect putatively ascribed to the disruption to CD44/HA interactions; for example, this is the proposed mechanism of action for the humanized recombinant RG7356PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFuZzwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl

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ZT4A

ADDIN EN.CITE.DATA [16]. A number of CD44 monoclonal antibodies are commercially available, some being specific to one variant (e.g. the tumor-associated CD44v6 for VFF-7PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DYXJib2duYW5pPC9BdXRob3I+PFllYXI+MTk5ODwvWWVh

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ADDIN EN.CITE.DATA [17], or CD44v10 for MEM-85 ADDIN EN.CITE <EndNote><Cite><Author>Skerlova</Author><Year>2015</Year><RecNum>65</RecNum><DisplayText><style face="superscript">[18]</style></DisplayText><record><rec-number>65</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1470592736">65</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Skerlova, J.</author><author>Kral, V.</author><author>Kachala, M.</author><author>Fabry, M.</author><author>Bumba, L.</author><author>Svergun, D. I.</author><author>Tosner, Z.</author><author>Veverka, V.</author><author>Rezacova, P.</author></authors></contributors><titles><title>Molecular mechanism for the action of the anti-CD44 monoclonal antibody MEM-85</title><secondary-title>Journal of Structural Biology</secondary-title></titles><periodical><full-title>Journal of Structural Biology</full-title><abbr-1>J Struct Biol</abbr-1></periodical><pages>214-223</pages><volume>191</volume><number>2</number><dates><year>2015</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>1047-8477</isbn><accession-num>WOS:000359096700015</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000359096700015</url></related-urls></urls><electronic-resource-num>10.1016/j.jsb.2015.06.005</electronic-resource-num></record></Cite></EndNote>[18]), some having the non-variable region as the immunogen (e.g. RG7356). In a recent screening it has been shown that intermediate but not affinity often correlates to high tumour uptakePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HbGF0dDwvQXV0aG9yPjxZZWFyPjIwMTY8L1llYXI+PFJl

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ADDIN EN.CITE.DATA [19]. The drawbacks of antibodies are their potential immunogenicity, the possibly excessive specificity, which requires an appropriate patient stratification ADDIN EN.CITE <EndNote><Cite><Author>Birzele</Author><Year>2015</Year><RecNum>75</RecNum><DisplayText><style face="superscript">[20]</style></DisplayText><record><rec-number>75</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1470643443">75</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Birzele, F.</author><author>Voss, E.</author><author>Nopora, A.</author><author>Honold, K.</author><author>Heil, F.</author><author>Lohmann, S.</author><author>Verheul, H.</author><author>Le Tourneau, C.</author><author>Delord, J. P.</author><author>van Herpen, C.</author><author>Mahalingam, D.</author><author>Coveler, A. L.</author><author>Meresse, V.</author><author>Weigand, S.</author><author>Runza, V.</author><author>Cannarile, M.</author></authors></contributors><titles><title>CD44 Isoform Status Predicts Response to Treatment with Anti-CD44 Antibody in Cancer Patients</title><secondary-title>Clinical Cancer Research</secondary-title></titles><periodical><full-title>Clinical Cancer Research</full-title><abbr-1>Clin Cancer Res</abbr-1></periodical><pages>2753-2762</pages><volume>21</volume><number>12</number><dates><year>2015</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>1078-0432</isbn><accession-num>WOS:000357336600015</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000357336600015</url></related-urls></urls><electronic-resource-num>10.1158/1078-r-14-2141</electronic-resource-num></record></Cite></EndNote>[20], and the CD44 variability, as discussed for HA.HA-based systems can be more easily combined with a variety of active principles, and have a lower cost, whereas antibodies have intrinsic therapeutic activity and higher targeting efficiency. For both classes, we still do not fully understand how CD44 expression affects binding (strictu sensu targeting), and how this relates to internalization; in this study we tackle these issues, using our experience with particular chitosan/HA (CS/HA) nanoparticlesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbG1hbGlrPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

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ADDIN EN.CITE.DATA [21] and soluble HA ADDIN EN.CITE <EndNote><Cite><Author>Ouasti</Author><Year>2012</Year><RecNum>4</RecNum><DisplayText><style face="superscript">[22]</style></DisplayText><record><rec-number>4</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1465304180">4</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Ouasti, Sihem</author><author>Kingham, Paul J.</author><author>Terenghi, Giorgio</author><author>Tirelli, Nicola</author></authors></contributors><titles><title>The CD44/integrins interplay and the significance of receptor binding and re-presentation in the uptake of RGD-functionalized hyaluronic acid</title><secondary-title>Biomaterials</secondary-title></titles><periodical><full-title>Biomaterials</full-title><abbr-1>Biomaterials</abbr-1></periodical><pages>1120-1134</pages><volume>33</volume><number>4</number><dates><year>2012</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0142-9612</isbn><accession-num>WOS:000298273400013</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000298273400013</url></related-urls></urls><electronic-resource-num>10.1016/j.biomaterials.2011.10.009</electronic-resource-num></record></Cite></EndNote>[22]. Here we use macrophages as a cellular model, because a) macrophages have a high CD44 expression and play a major role in HA uptake and degradation ADDIN EN.CITE <EndNote><Cite><Author>Culty</Author><Year>1992</Year><RecNum>45</RecNum><DisplayText><style face="superscript">[23]</style></DisplayText><record><rec-number>45</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1468683310">45</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Culty, M.</author><author>Nguyen, H. A.</author><author>Underhill, C. B.</author></authors></contributors><auth-address>CULTY, M (reprint author), GEORGETOWN MED CTR,DEPT ANAT &amp; CELL BIOL,WASHINGTON,DC 20007, USA.</auth-address><titles><title>The hyaluronan receptor (CD44) participates in the uptake and degradation of hyaluronan</title><secondary-title>Journal of Cell Biology</secondary-title><alt-title>J. Cell Biol.</alt-title></titles><periodical><full-title>Journal of Cell Biology</full-title><abbr-1>J Cell Biol</abbr-1></periodical><pages>1055-1062</pages><volume>116</volume><number>4</number><keywords><keyword>simian virus-40-transformed 3t3-cells</keyword><keyword>monoclonal-antibodies</keyword><keyword>endothelial-cells</keyword><keyword>cultured-cells</keyword><keyword>lymph-node</keyword><keyword>3t3 cells</keyword><keyword>binding</keyword><keyword>surface</keyword><keyword>glycoprotein</keyword><keyword>aggregation</keyword><keyword>Cell Biology</keyword></keywords><dates><year>1992</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0021-9525</isbn><accession-num>WOS:A1992HD55000020</accession-num><work-type>Article</work-type><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:A1992HD55000020</url></related-urls></urls><electronic-resource-num>10.1083/jcb.116.4.1055</electronic-resource-num><language>English</language></record></Cite></EndNote>[23]; b) they should offer considerably less variability in CD44 structure and behaviour than cancer cells, therefore they are an easier starting point; c) they are the prototypical off-target destination for any carrier-based therapy, therefore understanding their interactions with HA is important for the design of carriers with improved pharmacokinetics; d) they can be therapeutic targets themselves, if the (M2-like) tumour-associated macrophages are reprogrammed into a potentially tumoricidal (M1-like) phenotypePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb2dlcnM8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [26], but the human translatability of their classical or alternative activation is questionable. We have employed the human THP-1 cell line because: a) these premonocytes show commitment towards macrophage lineagesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BdXdlcng8L0F1dGhvcj48WWVhcj4xOTkxPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [27, 28], c) their polarization has been studied rather extensively, and in particular the alternatively activated THP-1 cells are often regarded as a reasonable model of tumour-associated macrophages ADDIN EN.CITE <EndNote><Cite><Author>Genin</Author><Year>2015</Year><RecNum>19</RecNum><DisplayText><style face="superscript">[29]</style></DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1465304181">19</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Genin, Marie</author><author>Clement, Francois</author><author>Fattaccioli, Antoine</author><author>Raes, Martine</author><author>Michiels, Carine</author></authors></contributors><titles><title>M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide</title><secondary-title>Bmc Cancer</secondary-title></titles><periodical><full-title>Bmc Cancer</full-title></periodical><volume>15</volume><dates><year>2015</year><pub-dates><date>Aug 8</date></pub-dates></dates><isbn>1471-2407</isbn><accession-num>WOS:000359099300001</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000359099300001</url></related-urls></urls><custom7>577</custom7><electronic-resource-num>10.1186/s12885-015-1546-9</electronic-resource-num></record></Cite></EndNote>[29]. However, to date there is no consensus about the conditions for THP-1 in vitro polarization; for example, differentiating (phorbol 12-myristate-13-acetate, PMA) and polarizing (lipopolysaccharides, LPS, and IFN-γ for M1; IL-4 and IL-13 for M2) have been used in co-incubationPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Uaml1PC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA [30] or in sequential treatments ADDIN EN.CITE <EndNote><Cite><Author>Genin</Author><Year>2015</Year><RecNum>19</RecNum><DisplayText><style face="superscript">[29]</style></DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1465304181">19</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Genin, Marie</author><author>Clement, Francois</author><author>Fattaccioli, Antoine</author><author>Raes, Martine</author><author>Michiels, Carine</author></authors></contributors><titles><title>M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide</title><secondary-title>Bmc Cancer</secondary-title></titles><periodical><full-title>Bmc Cancer</full-title></periodical><volume>15</volume><dates><year>2015</year><pub-dates><date>Aug 8</date></pub-dates></dates><isbn>1471-2407</isbn><accession-num>WOS:000359099300001</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000359099300001</url></related-urls></urls><custom7>577</custom7><electronic-resource-num>10.1186/s12885-015-1546-9</electronic-resource-num></record></Cite></EndNote>[29], nominally obtaining the same kind of activation, but without a quantitative comparison of the relevant phenotype markers. For this reason, we have first comparatively evaluated a set of protocols with the aim to maximize the morphological and biochemical differences between differently polarized THP-1 macrophages, and study how macrophage polarization may affect the expression of CD44. Then, we have set out to establish a qualitative link between CD44 presence and the different phases of uptake (binding and internalization) of both soluble HA and HA-based nanoparticles. 2. Results and discussion2.1 The cellular modelWe have used two different differentiation/polarization protocols (Fig. 1A) :1) a 24h combined treatment (used e.g. by Tjiu et al. for M2 THP-1PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Uaml1PC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA [30]) referred to as [6/18]; premonocytes (Mo) were first incubated with PMA (6h), then with PMA + polarizing factors (18h). 2) a 48h sequential treatment (similar to that used by Genin et al. to obtain M1 and M2 THP-1 ADDIN EN.CITE <EndNote><Cite><Author>Genin</Author><Year>2015</Year><RecNum>19</RecNum><DisplayText><style face="superscript">[29]</style></DisplayText><record><rec-number>19</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1465304181">19</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Genin, Marie</author><author>Clement, Francois</author><author>Fattaccioli, Antoine</author><author>Raes, Martine</author><author>Michiels, Carine</author></authors></contributors><titles><title>M1 and M2 macrophages derived from THP-1 cells differentially modulate the response of cancer cells to etoposide</title><secondary-title>Bmc Cancer</secondary-title></titles><periodical><full-title>Bmc Cancer</full-title></periodical><volume>15</volume><dates><year>2015</year><pub-dates><date>Aug 8</date></pub-dates></dates><isbn>1471-2407</isbn><accession-num>WOS:000359099300001</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000359099300001</url></related-urls></urls><custom7>577</custom7><electronic-resource-num>10.1186/s12885-015-1546-9</electronic-resource-num></record></Cite></EndNote>[29] or by Martinez et al. on primary cells ADDIN EN.CITE <EndNote><Cite><Author>Martinez</Author><Year>2006</Year><RecNum>22</RecNum><DisplayText><style face="superscript">[31]</style></DisplayText><record><rec-number>22</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1465304181">22</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Martinez, F. O.</author><author>Gordon, S.</author><author>Locati, M.</author><author>Mantovani, A.</author></authors></contributors><auth-address>Locati, M&#xD;Ist Clin Humanitas, Via Manzoni 56, I-20089 Rozzano, Italy&#xD;Ist Clin Humanitas, Via Manzoni 56, I-20089 Rozzano, Italy&#xD;Ist Clin Humanitas, I-20089 Rozzano, Italy&#xD;Univ Milan, Inst Gen Pathol, Milan, Italy&#xD;Univ Oxford, Sir William Dunn Sch Pathol, Oxford, England</auth-address><titles><title>Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: New molecules and patterns of gene expression</title><secondary-title>Journal of Immunology</secondary-title><alt-title>J Immunol</alt-title></titles><periodical><full-title>Journal of Immunology</full-title><abbr-1>J Immunol</abbr-1></periodical><alt-periodical><full-title>Journal of Immunology</full-title><abbr-1>J Immunol</abbr-1></alt-periodical><pages>7303-7311</pages><volume>177</volume><number>10</number><keywords><keyword>induced indoleamine 2,3-dioxygenase</keyword><keyword>colony-stimulating factors</keyword><keyword>dendritic cell maturation</keyword><keyword>antigen-presenting cells</keyword><keyword>alternative activation</keyword><keyword>receptor expression</keyword><keyword>interferon-gamma</keyword><keyword>nitric-oxide</keyword><keyword>ifn-gamma</keyword><keyword>murine</keyword></keywords><dates><year>2006</year><pub-dates><date>Nov 15</date></pub-dates></dates><isbn>0022-1767</isbn><accession-num>ISI:000242009700084</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://000242009700084</url></related-urls></urls><language>English</language></record></Cite></EndNote>[31]) referred to as [24/24], where premonocytes were first incubated with PMA alone (24h), then with polarizing factors alone (24h). In order for all cells to experience the same overall treatment duration (48h), in some cases we have employed a final resting phase: [6/18] macrophages were cultured for additional 24h in full medium, and so were also M0 macrophages (24h PMA differentiaton, 24h resting: protocol [24]). Conversely, in some cases such as the sequential [24/24] treatment, the cells were not subjected to any resting time. Since the presence or absence of a resting time can be important (M1-like polarization arises in THP-1 after a 5-day resting following a 24h treatment with 200 nM120 ng/mL PMA)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EYWlnbmVhdWx0PC9BdXRob3I+PFllYXI+MjAxMDwvWWVh

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ADDIN EN.CITE.DATA [28], we have also subjected M0 to a 48h recovery in a protocol is referred to as [24]*: any difference with [24] treatment will reflect the effect of a prolonged resting.Cell viability. None of the treatments leading to M0 and M2 phenotypes affected cell viability, whereas a moderate reduction was observed for M1: about 20% of dead cells were seen in live/dead assays, whereas MTS recorded a 30% decrease in average mitochondrial activity (see Supporting Information, Fig. S1). Cell morphology (Fig 1B and C). M0 and M2 macrophages exhibited almost identically round bodies (high solidity and thickness, low surface area; Fig. 1B, left) and similar morphology (Fig. 1B, right) on plastic, and also similar cellular size and granularity in suspension (Fig. 1C, right; , see the caption for parameter definitions), always without noticeable differences between the two polarization protocols. M1 were flatter and more spread, indicating a higher adhesion to the substrate, and were larger and more granular in suspension, with the M1 vs. M0 / M2 differences being larger under the [24/24] protocol. Finally, the length of the resting phase ([24] vs. [24]* for M0) had no effect.Fig. SEQ Figure \* ARABIC 1. THP-1 differentiation/polarization protocols and their effect on morphological markers. A: Summary of the protocols used to differentiate premonocytic THP-1 cells into resting (M0; PMA), classically activated (M1; LPS+IFN-γ), and alternatively activated (M2; IL-4+IL-13) macrophages. Representative phase contrast images are shown for the different phenotypes (Scale bars: 25 ?m). B: Morphological analysis. Left: Cell area, thickness, and solidity were employed as morphological descriptors; only M1 provided significantly different values, resp. vs. M2 in the [6/18] protocol, and vs. M2 and M0 in the [24/24] and [24] protocols; no significant difference was recorded between the two differentiation/polarization protocols. Right: Confocal images (Top view of volumetric reconstruction) of THP-1 macrophages representing nuclei (blue) and F-actin (green). A greater number of pseudopodia and flattened cells was observed in M1. M2 and M0 were very similar, with a slightly more developed F-actin network for M2 as the only visible difference C: Flow cytometry. Left: The contour plots show clear shifts in Forward Scattered Light (FSC) and Side Scattered Light (SSC) upon differentiation/polarization. The FSC/SSC plot for untreated premonocytes was used to define four arbitrary quadrants (Q1-Q4). Right: The results are summarized in histograms of granularity and size (top; granularity defined as (Q1+Q2)/(Q3+Q4)) and size (bottom; size defined as (Q2+Q3)/(Q1+Q4)). n=3. Surface markers (Fig. 2). In short, the three markers employed were all present in larger amounts under the [24/24] protocol.A) CD14 (LPS co-receptor, Fig. 2A) is a differentiation marker for the myelomonocytic stem cell line ADDIN EN.CITE <EndNote><Cite><Author>Zieglerheitbrock</Author><Year>1993</Year><RecNum>40</RecNum><DisplayText><style face="superscript">[32]</style></DisplayText><record><rec-number>40</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1465746481">40</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zieglerheitbrock, H. W. L.</author><author>Ulevitch, R. J.</author></authors></contributors><auth-address>SCRIPPS RES INST, LA JOLLA, CA 92037 USA.&#xD;ZIEGLERHEITBROCK, HWL (reprint author), INST IMMUNOL, GOETHESTR 31, W-8000 MUNICH 2, GERMANY.</auth-address><titles><title>CD14 - Cell-surface receptor and differentiation marker </title><secondary-title>Immunology Today</secondary-title><alt-title>Immunol. Today</alt-title></titles><periodical><full-title>Immunology Today</full-title><abbr-1>Immunol. Today</abbr-1></periodical><alt-periodical><full-title>Immunology Today</full-title><abbr-1>Immunol. Today</abbr-1></alt-periodical><pages>121-125</pages><volume>14</volume><number>3</number><keywords><keyword>human mononuclear phagocytes</keyword><keyword>lipopolysaccharide binding-protein</keyword><keyword>acute</keyword><keyword>myeloblastic-leukemia</keyword><keyword>human peripheral-blood</keyword><keyword>human-monocytes</keyword><keyword>monoclonal-antibodies</keyword><keyword>antigen cd14</keyword><keyword>invitro differentiation</keyword><keyword>signal</keyword><keyword>transduction</keyword><keyword>interferon-gamma</keyword><keyword>Immunology</keyword></keywords><dates><year>1993</year><pub-dates><date>Mar</date></pub-dates></dates><isbn>0167-5699</isbn><accession-num>WOS:A1993KQ27100008</accession-num><work-type>Review</work-type><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:A1993KQ27100008</url></related-urls></urls><electronic-resource-num>10.1016/0167-5699(93)90212-4</electronic-resource-num><language>English</language></record></Cite></EndNote>[32]; more specifically, its upregulation marks the THP-1 premonocyte-to-macrophage differentiationPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXJrPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA [28, 33, 34], although at low PMA doses this may not be observed (e.g. in Aldo et al. ADDIN EN.CITE <EndNote><Cite><Author>Culty</Author><Year>1992</Year><RecNum>45</RecNum><DisplayText><style face="superscript">[23]</style></DisplayText><record><rec-number>45</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1468683310">45</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Culty, M.</author><author>Nguyen, H. A.</author><author>Underhill, C. B.</author></authors></contributors><auth-address>CULTY, M (reprint author), GEORGETOWN MED CTR,DEPT ANAT &amp; CELL BIOL,WASHINGTON,DC 20007, USA.</auth-address><titles><title>The hyaluronan receptor (CD44) participates in the uptake and degradation of hyaluronan</title><secondary-title>Journal of Cell Biology</secondary-title><alt-title>J. Cell Biol.</alt-title></titles><periodical><full-title>Journal of Cell Biology</full-title><abbr-1>J Cell Biol</abbr-1></periodical><pages>1055-1062</pages><volume>116</volume><number>4</number><keywords><keyword>simian virus-40-transformed 3t3-cells</keyword><keyword>monoclonal-antibodies</keyword><keyword>endothelial-cells</keyword><keyword>cultured-cells</keyword><keyword>lymph-node</keyword><keyword>3t3 cells</keyword><keyword>binding</keyword><keyword>surface</keyword><keyword>glycoprotein</keyword><keyword>aggregation</keyword><keyword>Cell Biology</keyword></keywords><dates><year>1992</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>0021-9525</isbn><accession-num>WOS:A1992HD55000020</accession-num><work-type>Article</work-type><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:A1992HD55000020</url></related-urls></urls><electronic-resource-num>10.1083/jcb.116.4.1055</electronic-resource-num><language>English</language></record></Cite></EndNote>[23]: same cell density as here, but ten times less PMAPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA [35]). While the [24/24] protocol significantly upregulated CD14 with a predominantly CD14+ cell population for both M1 and M2, under the [6/18] protocol its level was indistinguishable from that of the parent Mo cells. Since M0 [24]* macrophages (24h additional resting time) showed a 3-fold higher CD14 than the M0 [24] ones, mechanistically we are inclined to ascribe the [24/24] better performance to its longer duration. It is also worth noting that CD14 was higher in the M1 ADDIN EN.CITE <EndNote><Cite><Author>Rey-Giraud</Author><Year>2012</Year><RecNum>29</RecNum><DisplayText><style face="superscript">[36]</style></DisplayText><record><rec-number>29</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1465304181">29</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rey-Giraud, F.</author><author>Hafner, M.</author><author>Ries, C. H.</author></authors></contributors><auth-address>Rey-Giraud, F&#xD;Roche Diagnost GmbH, Pharma Res &amp; Early Dev, Penzberg, Germany&#xD;Roche Diagnost GmbH, Pharma Res &amp; Early Dev, Penzberg, Germany&#xD;Roche Diagnost GmbH, Pharma Res &amp; Early Dev, Penzberg, Germany&#xD;Mannheim Univ Appl Sci, Inst Mol &amp; Cell Biol, Mannheim, Germany</auth-address><titles><title>In vitro generation of monocyte-derived macrophages under serum-free conditions improves their tumor promoting functions</title><secondary-title>Plos One</secondary-title><alt-title>Plos One</alt-title></titles><periodical><full-title>Plos One</full-title><abbr-1>Plos One</abbr-1></periodical><alt-periodical><full-title>Plos One</full-title><abbr-1>Plos One</abbr-1></alt-periodical><volume>7</volume><number>8</number><keywords><keyword>colony-stimulating factor</keyword><keyword>dendritic cells</keyword><keyword>m2 macrophages</keyword><keyword>interferon-gamma</keyword><keyword>iron homeostasis</keyword><keyword>polarization</keyword><keyword>activation</keyword><keyword>differentiation</keyword><keyword>progression</keyword><keyword>receptors</keyword></keywords><dates><year>2012</year><pub-dates><date>Aug 6</date></pub-dates></dates><isbn>1932-6203</isbn><accession-num>ISI:000307810000057</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://000307810000057</url></related-urls></urls><electronic-resource-num>ARTN e42656&#xD;10.1371/journal.pone.0042656</electronic-resource-num><language>English</language></record></Cite></EndNote>[36] than in the M2 statePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYXJ0aW5lejwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+

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ADDIN EN.CITE.DATA [38]); it is induced in macrophage maturation, and it is typically upregulated with PMA ADDIN EN.CITE <EndNote><Cite><Author>Prieto</Author><Year>1994</Year><RecNum>31</RecNum><DisplayText><style face="superscript">[39]</style></DisplayText><record><rec-number>31</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1465304181">31</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Prieto, J.</author><author>Eklund, A.</author><author>Patarroyo, M.</author></authors></contributors><auth-address>Prieto, J&#xD;Karolinska Inst,Dept Immunol,S-10401 Stockholm,Sweden&#xD;Karolinska Inst,Dept Immunol,S-10401 Stockholm,Sweden&#xD;Karolinska Hosp,Dept Thorac Med,S-10401 Stockholm,Sweden</auth-address><titles><title>Regulated expression of integrins and other adhesion molecules during differentiation of monocytes into macrophages</title><secondary-title>Cellular Immunology</secondary-title><alt-title>Cell Immunol</alt-title></titles><periodical><full-title>Cellular Immunology</full-title><abbr-1>Cell Immunol</abbr-1></periodical><alt-periodical><full-title>Cellular Immunology</full-title><abbr-1>Cell Immunol</abbr-1></alt-periodical><pages>191-211</pages><volume>156</volume><number>1</number><keywords><keyword>human alveolar macrophages</keyword><keyword>cell-surface</keyword><keyword>pulmonary sarcoidosis</keyword><keyword>glycoprotein family</keyword><keyword>beta-2 integrins</keyword><keyword>peripheral-blood</keyword><keyword>phorbol diester</keyword><keyword>antigen-1 lfa-1</keyword><keyword>leukemia-cells</keyword><keyword>lymphocytes</keyword></keywords><dates><year>1994</year><pub-dates><date>Jun</date></pub-dates></dates><isbn>0008-8749</isbn><accession-num>ISI:A1994NP11700017</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://A1994NP11700017</url></related-urls></urls><electronic-resource-num>DOI 10.1006/cimm.1994.1164</electronic-resource-num><language>English</language></record></Cite></EndNote>[39]. Our results confirmed both its presence in Mo and its upregulation as the result of maturation processes. The resting time did not seem to play a major role (similar levels in [24] and [24]* M0), therefore the much larger CD11c expression in [24/24] vs. [6/18] is ascribed to a greater efficacy of the sequential stimulation. Last, it is noteworthy that the very large CD11c presence observed in the [24/24] M2 polarization appears to mirror what reported in the M2a induction from primary cellsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CYWk8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA [28].Fig. 2. THP-1 macrophage markers; please note that thermosensitive substrates were employed in order to avoid degradation and/or removal of surface proteins. A to D: The expression of CD14 (A), CD11c (B), CD206 (C) and CD44 (D) on THP-1 was evaluated via flow cytometry using primary antibodies. The Median Fluorescence Intensity (MFI) for PMA-treated (M0), LPS+IFN-γ-treated (M1), and IL-4+IL-13-treated (M2) cells is expressed in relation to that of their parent, untreated monocytes (blue horizontal bar). E: The levels of TNF-α, IL-1β and TGF-1 were measured via ELISA. Notice that the differences in terms of both marker expression and release of cytokines were not affected by differences in cell viability for the two experimental protocols (see Supporting Information, section SI1 and Fig. S1). Data are presented as average SD of n=3 experiments (flow cytometry) and of n=4 experiments (ELISA). The statistical analysis refers to the comparison of receptor expression in different polarizations: ***P<0.001, **P<0.01, *P<0.05 (Two-way ANOVA).Cytokine profiling. Three cytokines (TNF-α, IL-1β and TGF-1, Fig. 2E) were analyzed for a final assessment of the polarization into pro-inflammatory and anti-inflammatory subtypes; a fourth marker, IL-10, was under the detection limit for the three macrophagic polarizations (data not shown), which may be a peculiarity of THP-1 ADDIN EN.CITE <EndNote><Cite><Author>Schildberger</Author><Year>2013</Year><RecNum>26</RecNum><DisplayText><style face="superscript">[42]</style></DisplayText><record><rec-number>26</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1465304181">26</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Schildberger, A.</author><author>Rossmanith, E.</author><author>Eichhorn, T.</author><author>Strassl, K.</author><author>Weber, V.</author></authors></contributors><auth-address>Danube Univ Krems, Ctr Biomed Technol, Dept Hlth Sci &amp; Biomed, A-3500 Krems, Austria&#xD;Danube Univ Krems, Christian Doppler Lab Innovat Therapy Approache S, A-3500 Krems, Austria</auth-address><titles><title>Monocytes, peripheral blood mononuclear cells, and THP-1 cells exhibit different cytokine expression patterns following stimulation with lipopolysaccharide</title><secondary-title>Mediators of Inflammation</secondary-title><alt-title>Mediat Inflamm</alt-title></titles><periodical><full-title>Mediators of Inflammation</full-title><abbr-1>Mediat Inflamm</abbr-1></periodical><alt-periodical><full-title>Mediators of Inflammation</full-title><abbr-1>Mediat Inflamm</abbr-1></alt-periodical><keywords><keyword>human endothelial-cells</keyword><keyword>experimental sepsis</keyword><keyword>adhesion</keyword><keyword>model</keyword><keyword>inflammation</keyword><keyword>macrophages</keyword><keyword>activation</keyword><keyword>mechanisms</keyword><keyword>mediators</keyword><keyword>receptor</keyword></keywords><dates><year>2013</year></dates><isbn>0962-9351</isbn><accession-num>ISI:000320242600001</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://000320242600001</url></related-urls></urls><electronic-resource-num>Artn 697972&#xD;10.1155/2013/697972</electronic-resource-num><language>English</language></record></Cite></EndNote>[42] (in addition to what seen for CD206). In short, the two polarization protocols were largely similar. Not surprisingly, the highest levels of pro-inflammatory cytokines (TNF-α and IL-1β) were detected for the M1 phenotype, while being lower for M0 and lowest for M2 macrophages. M2 macrophages showed the highest levels of (latent) TGF-1. On the grounds of the increased upregulation of all differentiation markers, the [24/24] protocol was chosen for all further polarization experiments, using the analogous [24] protocol for M0 polarization. 2.2. Expression of CD44 and of its isoformsCD44 was already present in Mo, but its expression increased upon their differentiation (see Supporting Information, Fig.S2; see also literature reportsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaW9ub3Y8L0F1dGhvcj48WWVhcj4xOTk4PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA [43], also for its higher HA affinity ADDIN EN.CITE <EndNote><Cite><Author>Levesque</Author><Year>1997</Year><RecNum>46</RecNum><DisplayText><style face="superscript">[44]</style></DisplayText><record><rec-number>46</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1468687063">46</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Levesque, M. C.</author><author>Haynes, B. F.</author></authors></contributors><auth-address>Duke Univ, Med Ctr, Dept Med, Div Rheumatol Allergy &amp; Clin Immunol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Immunol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Arthrit Ctr, Durham, NC 27710 USA.&#xD;Haynes, BF (reprint author), Duke Univ, Med Ctr, Dept Med, Div Rheumatol Allergy &amp; Clin Immunol, Box 3258, Durham, NC 27710 USA.</auth-address><titles><title>Cytokine induction of the ability of human monocyte CD44 to bind hyaluronan is mediated primarily by TNF-alpha and is inhibited by IL-4 and IL-13</title><secondary-title>Journal of Immunology</secondary-title><alt-title>J. Immunol.</alt-title></titles><periodical><full-title>Journal of Immunology</full-title><abbr-1>J Immunol</abbr-1></periodical><pages>6184-6194</pages><volume>159</volume><number>12</number><keywords><keyword>t-cell activation</keyword><keyword>tumor-necrosis-factor</keyword><keyword>chimeric monoclonal-antibody</keyword><keyword>rheumatoid-arthritis</keyword><keyword>extracellular-matrix</keyword><keyword>murine macrophages</keyword><keyword>adhesion</keyword><keyword>molecule</keyword><keyword>growth-factor</keyword><keyword>acid binding</keyword><keyword>receptor</keyword><keyword>Immunology</keyword></keywords><dates><year>1997</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0022-1767</isbn><accession-num>WOS:000071914900054</accession-num><work-type>Article</work-type><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000071914900054</url></related-urls></urls><language>English</language></record></Cite></EndNote>[44]).CD44 exhibited a punctuated fluorescence preferentially localized at or close to the cell surface, without any noticeable difference in the three polarizations (red in Fig. 3A); qualitatively, CD44 appeared to be present in larger amounts in M1, and this was then quantitatively confirmed via various techniques: 1) Western blotting (Fig. 3B) indicated CD44 expression in the order M1 > M0 > M2 ≥ Mo. In comparison to Mo premonocytes, M0 showed a 3.5-fold increase, M1 a 5.5-fold increase for M1, and M2 a 1.25-fold increase. 2) Direct staining flow cytometry (Fig. 3C) and 3) indirect staining flow cytometry (Fig. 3D) provided a similar picture, with the only difference that CD44 expression in M0 and M2 is statistically indistinguishable, confirming literature reports that it remains largely unaffected by alternative activation PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SdWZmZWxsPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48

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ADDIN EN.CITE.DATA [45] In terms of CD44 splice variants, the absence of intense secondary bands in the Western blots (Fig. 3B) already suggests standard CD44 (~85-90 kDa) to be the predominant isoform. We have confirmed this by assessed the presence of some CD44 variants (CD44v3, v4 and v6, among the most relevant in cancerPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYW5nPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA [46]) in relation to the total CD44 (Figure 3D). These isoforms appeared to be marginally present in Mo, and substantially absent in M1 and M2, with one notable exception: at least 60% of the M2 population was positive to CD44v6, which showed a peripheral/membrane localization virtually identical to that of the standard variant (Fig. 3E). Although never clearly associated to M2, the scarce evidence about the expression of CD44v6 in macrophages aligns with our finding: this variant (in a soluble form) was found to be produced in monocytes undergoing macrophagic differentiationPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CcmF1bXVsbGVyPC9BdXRob3I+PFllYXI+MjAwMDwvWWVh

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ADDIN EN.CITE.DATA [48]. Besides the possible use of CD44v6 as a marker of THP-1 M2 polarization, it is tempting to think at its utility for M2 macrophage targeting.Fig. 3. CD44 expression in THP-1 cells. A: Confocal Microscopy: volume rendering of THP-1 showing nuclei (blue), F-actin (green) and CD44 (red) (experimental protocol: see Experimental Section, section 4.6). B: Representative CD44 Western blot (right) of untreated (Mo), M0[24], M1[24/24] and M2[24/24] cells. β-actin was used as loading control. Averages SD (n=3) reported in the left panel. C: Expression of CD44 obtained via direct staining flow cytometry (APC-labelled anti-CD44 mAb). Incidentally, these data are analogous to the expression recorded using [6/18] and [24]* protocols (see Supporting Information, Fig.S2). Average SD (n=3). C. Expression of total CD44 (CD44pan; same stain as for Western blotting) and CD44 variants (CD44v3, CD44v4, and CD44v6) by flow cytometry after indirect staining with AlexaFluor?647 (AF647). The cells were detached using an enzyme-free protocol, which provided quantitative cell recovery while maintaining full viability (see Supporting Information, section SI3 and Fig.S3). Histogram of n-fold change in median fluorescence intensity (MFI) over isotype control (left), and percentage of positive cells for the various cell populations (right). n=3. For more complete data, see Supporting Information, Fig. S4. For the statistical comparison: ***P<0.001, **P<0.01 (One-way ANOVA) in the comparison between the three highlighted peaks and the isoform presence in other polarizations. E: Confocal images of CD44 indirect staining of THP-1 with anti-mouse IgG (whole molecule)–FITC; all images were acquired with sequential scans keeping constant the following settings Ex(power)/Em[adjusted mirrors]: a) DAPI Ex/Em 405(10%)/[410-460]nm, b) CD44tot/CD44v6 488(30%)/[500-550]nm. Merge of fluorescent acquisition of the first 5 m from cellular basal layer (scale bars: 15 m).2.3. Complex relation between uptake of HA materials and CD44 expressionWe have prepared rhodamine-labelled HA (HA-Rho; Mw = 180 kDa, 0.7% mol functionalization), and used it as such as a soluble ligand, or in the form of chitosan/HA (CS/HA) nanoparticles. The latter were produced via direct polyelectrolyte complexation, employing CS with two different molecular weights, and were loaded with a DY547-labelled siRNA, in order to provide a generic model for HA-decorated nanocarriers. Please note that they differ from soluble HA both in size and in surface density of CD44-binding groups (HA is more condensed when bound to CS).We have followed the uptake kinetics of both soluble HA and of CS/HA nanoparticles by monitoring their fluorescence in cell lysates and via flow cytometry after trypsinization. The fluorescence of cell lysates accounts for both surface bound and internalized material; on the contrary, due to the trypsin-mediated degradation of CD44 ADDIN EN.CITE <EndNote><Cite><Author>Biddle</Author><Year>2013</Year><RecNum>36</RecNum><DisplayText><style face="superscript">[49]</style></DisplayText><record><rec-number>36</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1465304181">36</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Biddle, A.</author><author>Gammon, L.</author><author>Fazil, B.</author><author>Mackenzie, I. C.</author></authors></contributors><auth-address>Queen Mary Univ London, Barts &amp; London Sch Med &amp; Dent, Blizard Inst, London, England&#xD;Univ Bergen, Haukeland Univ Hosp, Gade Inst, Bergen, Norway</auth-address><titles><title>CD44 Staining of Cancer Stem-Like Cells Is Influenced by Down-Regulation of CD44 Variant Isoforms and Up-Regulation of the Standard CD44 Isoform in the Population of Cells That Have Undergone Epithelial-to-Mesenchymal Transition</title><secondary-title>Plos One</secondary-title><alt-title>Plos One</alt-title></titles><periodical><full-title>Plos One</full-title><abbr-1>Plos One</abbr-1></periodical><alt-periodical><full-title>Plos One</full-title><abbr-1>Plos One</abbr-1></alt-periodical><volume>8</volume><number>2</number><keywords><keyword>human colorectal-cancer</keyword><keyword>breast-cancer</keyword><keyword>prospective identification</keyword><keyword>pancreatic-cancer</keyword><keyword>melanoma-cells</keyword><keyword>neck-cancer</keyword><keyword>carcinoma</keyword><keyword>head</keyword><keyword>metastasis</keyword><keyword>growth</keyword></keywords><dates><year>2013</year><pub-dates><date>Feb 20</date></pub-dates></dates><isbn>1932-6203</isbn><accession-num>WOS:000315184200241</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000315184200241</url></related-urls></urls><electronic-resource-num>ARTN e57314&#xD;10.1371/journal.pone.0057314</electronic-resource-num><language>English</language></record></Cite></EndNote>[49] and the ensuing removal of membrane-bound HA ADDIN EN.CITE <EndNote><Cite><Author>Knudson</Author><Year>2002</Year><RecNum>37</RecNum><DisplayText><style face="superscript">[50]</style></DisplayText><record><rec-number>37</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1465304181">37</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Knudson, C. B.</author><author>Rousche, K. T.</author><author>Peterson, R. S.</author><author>Chow, G.</author><author>Knudson, W.</author></authors><secondary-authors><author>Hascall, V. C.</author><author>Kuettner, K. E.</author></secondary-authors></contributors><auth-address>Knudson, CB&#xD;Rush Med Coll, Dept Biochem, 1653 W Congress Pkwy, Chicago, IL 60612 USA&#xD;Rush Med Coll, Dept Biochem, 1653 W Congress Pkwy, Chicago, IL 60612 USA&#xD;Rush Med Coll, Dept Biochem, Chicago, IL 60612 USA</auth-address><titles><title>CD44 and cartilage matrix stabilization</title><secondary-title>Many Faces of Osteoarthritis</secondary-title><tertiary-title>Methods and Tools in Biosciences and Medicine</tertiary-title></titles><periodical><full-title>Many Faces of Osteoarthritis</full-title></periodical><pages>219-230</pages><keywords><keyword>receptor-mediated endocytosis</keyword><keyword>human articular chondrocytes</keyword><keyword>hyaluronan receptor</keyword><keyword>pericellular matrix</keyword><keyword>homing receptor</keyword><keyword>antisense inhibition</keyword><keyword>extracellular-matrix</keyword><keyword>cytoplasmic domain</keyword><keyword>glycoprotein cd44</keyword><keyword>ankyrin-binding</keyword></keywords><dates><year>2002</year></dates><publisher>Birkh?user</publisher><accession-num>WOS:000181203200026</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000181203200026</url></related-urls></urls><language>English</language></record></Cite></EndNote>[50], we assume that flow cytometry predominantly refers to internalized HA. This assumption is confirmed by the negligible effect of an extracellular fluorescence quencher (trypan blue, data not shown) in flow cytometry experiments.For all the three macrophage polarizations, the fluorescence of cell lysates (black symbols in all panels of Fig. 5A) reached a plateau already at 2h for soluble HA and at 4h for nanoparticles, with virtually all cells being positive for internalized material.This indicates a rapid binding and saturation of the HA receptor(s), which we predominantly identify as CD44, due to the significant inhibition obtained with the Hermes-1 antibody, specifically for M1 and M2 (2h, HA-Rho fluorescence in cell lysates; Fig. 4D). Flow cytometry showed the internalization kinetics to proceed much more slowly (purple symbols in all panels of Fig. 5A). Since the 2h internalization appeared to be almost negligible, we have considered the 2h cell lysate data as an indication of the capacity of the three macrophage polarizations to bind free HA or CS/HA nanoparticles. On the other hand, we have used the 16h flow cytometry MFI as a measure of their internalization efficiency. We have then cross-correlated these data (binding and internalization) with their expression of CD44, as quantified via Western blotting and direct and indirect stain flow cytometry, for the three macrophage phenotypes (Fig. 4B).Fig. 4. A: Uptake of HA-Rho (left) and of CS/HA nanoparticles (centre and right) followed via through flow cytometry (purple) and fluorimetry of cell lysates (black; the lysate data are normalized against the protein content). Please note that the flow cytometry data of CS/HA nanoparticles are obtained by monitoring the fluorescence of the nanoparticle cargo i.e. DY547-labelled siRNA (purple). B: Cross-correlation between the expression of CD44 (CD44pan; measured through Western blotting and both direct and indirect stain. flow cytometry) and HA or CS/HA binding (cell lysate at 2h, top) and internalization (flow cytometry at 16h, bottom). Please note that the CD44 expression is normalized against M0 independently for each analytical technique. C: Confocal microscopy acquisitions of fixed THP-1 macrophages after incubation with HA-Rho for 16 hours and counter-staining with anti-CD44pan mAb. Scale bars: 10 m. D: Effect of CD44 antibody treatment on the uptake of HA-Rho. THP-1 macrophages were pre-treated with 20 μg/mL Hermes-I antibody followed by a 2 hour incubation with medium containing both 10 μg/mL antibody and 125 μg/mL HA-Rho (n=3). Statistical analysis: M1, **P=0.0005; M2, *P=0.00039 (Two-way ANOVA). The only partial inhibition is not a concern: a max 50% inhibition is common for Hermes-1, which is nevertheless one of the best means to reduce HA internalization in human cells ADDIN EN.CITE <EndNote><Cite><Author>Culty</Author><Year>1990</Year><RecNum>44</RecNum><DisplayText><style face="superscript">[51]</style></DisplayText><record><rec-number>44</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1466944609">44</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Culty, M.</author><author>Miyake, K.</author><author>Kincade, P. W.</author><author>Silorski, E.</author><author>Butcher, E. C.</author><author>Underhill, C.</author></authors></contributors><titles><title>The hyaluronate receptor is a member of the CD44 (H-CAM) familt of cell-surface glycoproteins</title><secondary-title>Journal of Cell Biology</secondary-title></titles><periodical><full-title>Journal of Cell Biology</full-title><abbr-1>J Cell Biol</abbr-1></periodical><pages>2765-2774</pages><volume>111</volume><number>6</number><dates><year>1990</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>0021-9525</isbn><accession-num>WOS:A1990ET17600050</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:A1990ET17600050</url></related-urls></urls><electronic-resource-num>10.1083/jcb.111.6.2765</electronic-resource-num></record></Cite></EndNote>[51]. The point is that only few anti-CD44 antibodies bind close enough to the LINK module to reduce HA uptake ADDIN EN.CITE <EndNote><Cite><Author>Liao</Author><Year>1995</Year><RecNum>43</RecNum><DisplayText><style face="superscript">[52]</style></DisplayText><record><rec-number>43</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1466895097">43</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Liao, H. X.</author><author>Lee, D. M.</author><author>Levesque, M. C.</author><author>Haynes, B. F.</author></authors></contributors><auth-address>LIAO, HX (reprint author), DUKE UNIV,MED CTR,DUKE ARTHRITIS CTR,DEPT MED,BOX 3258,DURHAM,NC 27710, USA.</auth-address><titles><title>N-terminal and central regions of the human CD44 extracellular domain participate in cell-surface hyaluronan-binding</title><secondary-title>Journal of Immunology</secondary-title><alt-title>J. Immunol.</alt-title></titles><periodical><full-title>Journal of Immunology</full-title><abbr-1>J Immunol</abbr-1></periodical><pages>3938-3945</pages><volume>155</volume><number>8</number><keywords><keyword>lymphocyte homing receptor</keyword><keyword>transmembrane glycoprotein gp85</keyword><keyword>cartilage</keyword><keyword>proteoglycan core</keyword><keyword>link protein</keyword><keyword>acid binding</keyword><keyword>molecular-cloning</keyword><keyword>splice</keyword><keyword>variants</keyword><keyword>antibodies</keyword><keyword>identification</keyword><keyword>activation</keyword><keyword>Immunology</keyword></keywords><dates><year>1995</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>0022-1767</isbn><accession-num>WOS:A1995RY58100031</accession-num><work-type>Article</work-type><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:A1995RY58100031</url></related-urls></urls><language>English</language></record></Cite></EndNote>[52].CD44 expression and HA binding showed a positive correlation (both M1>M0M2), more clearly for HA in a soluble form than when on the nanoparticles surface. 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ADDIN EN.CITE.DATA [53], but our data show also a link to its actual level of expression.Surprisingly, we have recorded a negative correlation between HA internalization and CD44 expression for all the three HA systems studied, i.e. the amount of internalized HA material appeared to reduce with increasing levels of CD44. This unexpected phenomenon could be due to HA internalization being mediated by receptors other than CD44, and the transfer of HA to these putative internalization receptors would require its de-complexation from CD44, which is likely to be slowed down by a larger CD44 expression. Indeed confocal microscopy showed that the co-localization between internalized HA and CD44 was rather limited (Fig. 4C), and it appeared to be higher for M1, which showed both the highest CD44 expression and the slowest internalization.3. ConclusionIn this study, we have validated a robust polarization method for THP-1 cells, and used them as an in vitro model to study the role of human macrophage polarization in the CD44-mediated uptake of HA-based systems. We have shown that the expression of CD44 is polarization-dependent; not only CD44v6 (normally associated with tumours) was found exclusively in M2 macrophages, but the overall CD44 amount scaled as M1 > M0 ≥ M2. Intriguingly, the same order was found in the capacity of macrophages to bind soluble HA and two kinds of HA-displaying nanoparticles, but their internalization appeared to follow an inverse order. This may profoundly affect the efficiency of a delivery approach: paradoxically, cells with the highest CD44 expression and potentially the best ‘binders’ may turn out to be the most difficult to e.g. transfect with a nucleic acid payload, because of the slower/more difficult internalization of the HA carrier structure.4. Experimental section4.1. General cell cultureThe human monocyte cell line THP-1 (TIB-202?) was purchased from ATCC (Manassas, VA, USA) and cultured in RPMI 1640 medium (#42402-016, Lot. #1454711, Gibco?/Invitrogen, UK) supplemented with 10% (v/v) foetal bovine serum (FBS, F7524, Lot #123M3399), 2 mM L-Glutamine (G7513), 1% (v/v) antibiotic-antimycotic solution (A9909), and 50 ?M 2-mercaptoethanol (M3148), all of them purchased from Sigma-Aldrich (UK), in a humidified 5% (v/v) CO2 air atmosphere at 37°C. The medium above is hereafter referred to as complete medium. Cells were maintained at densities under 1×106 cells/mL, split every 2-3 days following the supplier’s recommendations, and discarded upon reaching passage number 20. Preparation of 2X concentrated RPMI 1640 medium. 10.39 g of RPMI 1640 powder (Gibco, UK) were dissolved in 350 mL of distilled water, followed by addition of 2 g of NaHCO3 (ReagentPlus? ≥99.5%, powder, S8875, Sigma-Aldrich, UK) The pH was then adjusted to 7.1 by adding 1M HCl and the volume brought to 390 mL with distilled water. The resulting medium was filtered using Disposable Sterile Filter Systems 0.22 μm (Corning, UK) and supplemented accordingly (20% (v/v) FBS and 2% (v/v) antibiotic-antimycotic solution, referred to a final volume of 500 mL).4.2. Differentiation protocolsPMA concentration. PMA has been used at concentrations as high as 200 ng/mL (18h)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYXJvbnM8L0F1dGhvcj48WWVhcj4yMDA3PC9ZZWFyPjxS

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Y29yZD48L0NpdGU+PC9FbmROb3RlPn==

ADDIN EN.CITE.DATA [28], or as low as 25 nM (15 ng/mL, 48h)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MdW5kPC9BdXRob3I+PFllYXI+MjAxNjwvWWVhcj48UmVj

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YW5ndWFnZT48L3JlY29yZD48L0NpdGU+PC9FbmROb3RlPgB=

ADDIN EN.CITE.DATA [55] or 5 ng/mL (48h)PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXJrPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48UmVj

TnVtPjIzPC9SZWNOdW0+PERpc3BsYXlUZXh0PjxzdHlsZSBmYWNlPSJzdXBlcnNjcmlwdCI+WzMz

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ADDIN EN.CITE.DATA [33]; we have chosen an intermediate concentration (50 ng/mL) to avoid undesired gene upregulation seen with larger dosesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QYXJrPC9BdXRob3I+PFllYXI+MjAwNzwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA [33], but still provide a stable attachment of differentiated cells over the 24 hour period. Cell density. It has been observed that more homogeneous THP-1 populations can be obtained using relatively low (<1×106 cells/mL) premonocyte cell density PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbGRvPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA [35]; in this study we have employed 5×105 cells/mL, corresponding to 25×105 cells/cm2 in case of full attachment.A) For premonocyte – M0 differentiation, the cells were incubated for 24 hours with 50 ng·mL-1 phorbol 12-myristate 13-acetate (PMA; P1585, Sigma-Aldrich, UK) in complete medium. Differentiated, adherent cells were washed twice with serum-free medium and then rested for a further 24 or 48 hours in PMA-free complete medium to obtain resting macrophages respectively defined as M0[24] or M0[24]*. B) For premonocyte – M1 differentiation/polarization, in complete medium, the cells were treated either for 6 hours with 50 ng·mL-1 PMA, and then co-incubated with 100 ng·mL-1 Lipopolysaccharides (LPS) from E. coli O26:B6 (L8274, Lot. #032M4089V, Sigma-Aldrich, UK), 20 ng·mL-1 IFN- (#300-02, Lot #081427) and 50 ng·mL-1 PMA for the following 18 hours (followed by a 24h resting phase complete medium), or for 24 hours with 50 ng·mL-1 PMA, and with 100 ng·mL-1 LPS and 20 ng·mL-1 IFN- (no PMA) for the following 24 hours, to obtain classically activated macrophages respectively defined as M1[6/18] or M1[24/24]. C) For premonocyte – M2 differentiation/polarization, the cells were treated as in B) replacing LPS/IFN- with 20 ng·mL-1 IL-4 (#200-04, Lot #061314) and 20 ng·mL-1 IL-13 (#200-13, Lot #051023), obtaining alternatively activated macrophages defined as M2[6/18] or M2[24/24]. All the cytokines were purchased from Prepotech, Inc.4.3. Flow cytometry analysisA) Direct staining: THP-1 premonocytes were differentiated and polarized on Nunc UpCellTM 12-well themo-sensitive plates (Thermo-Scientific, UK), which allowed cell detachment and subsequent suspension by cooling at room temperature for 30 minutes. Approximately 0.5×106 cells were harvested in 100 μL FACS buffer (PBS supplemented with 2% (v/v) FBS and 0.1% (m/v) NaN3) per sample tube (1.5 mL Eppendorf tubes), incubated for 20 minutes on ice with Fc-receptor blocking inhibitor (#14-9161, Affymetrix/eBioscience, UK) and then stained for 30 minutes at room temperature with primary-conjugated antibodies: i) mouse anti-human CD44:APC (1:20) (Clone MEM-263; Abcam, UK), ii) CD11c:PerCP/Cy5.5 (1:40) (Clone Bu15; BioLegend, UK), iii) CD14:FITC (1:10) (Clone MEM-18; AbD Serotec, UK), and iv) (1:10) CD206:PE (Clone 15-2; BioLegend, UK). To wash off any excess/unbound antibody, two serial steps of centrifugation were used. The expression of surface markers was assessed on 10,000 live, individual cells with a CyAn? ADP analyzer using the Summit software (v 4.3, Beckman Coulter, Inc.). Data were analyzed with FlowJo (vX.0.7, Tree Star, Ashland, OR, USA) after gating live and single events in the FSC/SSC and Pulse width/FSC windows, respectively. The median fluorescence intensity (MFI) of the isotype control (Mouse IgG1; AbD Serotec, UK) was used as threshold to calculate the MFI of the marker of interest. Shifts in the FSC and SSC signal along macrophage differentiation and polarisation were also analyzed to evaluate phenotypical changes (cell size and inner cellular complexity). The same detachment procedure (without staining) was used to assess size and granularity for the morphological analysis.Indirect staining: THP-1 premonocytes were differentiated to M0[48], M1[24/24] and M2[24/24] in Costar? polystyrene 6-well plates (3506, Corning, UK). Cells were detached using pre-warmed Cell Dissociation Buffer, Enzyme-Free, PBS (#13151-014, Gibco?/Invitrogen, UK). Approximately 0.5×106 cells were suspended in 100 μL FACS buffer per sample tube (1.5 mL Eppendorf tubes), incubated for 20 minutes on ice with Fc-receptor blocking inhibitor (#14-9161, Affymetrix/eBioscience, UK) and stained for 30 minutes at room temperature with the primary antibodies: i) mouse anti-human CD44 (1:100) (156-3C11, Cell Signaling), ii) mouse anti-human CD44v3 (1:20) (Clone #3G5, R&D Systems), iii) mouse anti-human CD44v4 (1:50) (MCA1728; AbD Serotec), iv) mouse anti-human CD44v6 (1:20) (Clone #2F10, R&D Systems), or v) IgG1/IgG2 control (1:10) (AbD Serotec). Excess antibody was removed by centrifugation and cells were incubated for further 30 minutes at room temperature with the secondary antibody: goat anti-mouse IgG H&L, AlexaFluor?647-conjugated (1:2000) (ab150115, Abcam). The expression of these markers was detected on 10,000 live, individual cells using a BD LSRFortessa cytometer (BD Bioscience, San Jose CA, USA) equipped with the FACSDiva software (v8.0.1). Data were analysed with FlowJo (vX.0.7, Tree Star, Ashland, OR, USA) after gating live cells in the FSC/SSC window and singlets in the FSC-H/FSC-A window, respectively. The median fluorescence intensity (MFI) of the isotype control was used as threshold to calculate the MFI of the marker of interest.4.4. Western blot analysisTHP-1 premonocytes were differentiated and polarized in Costar? 25cm? polystyrene angled neck flasks (3056, Corning, UK). Total cell extracts were prepared in ice-cold RIPA Buffer (R0278, Sigma-Aldrich, UK) supplemented with cOmpleteUltra Tablets, Mini, EDTA-free EASYpack (#05892791001, Roche, Germany) and stored at -80°C until use. Equal amounts of protein (cell lysates) in Laemmli buffer containing 5% (v/v) 2-mercaptoethanol (M3148, Sigma-Aldrich, UK) were separated by 7.5% acrylamide SDS-PAGE using a Criterion? Cell (#165-6001; Run settings: 1 hour, 100V, 0.5 A) and transferred to a PVDF membrane (#162-0177 using a Criterion? Blotter (#170-4070; Run settings: 30 minutes, 100 V, 0.5 A). Membranes were blocked by incubation with 5% (w/v) non-fat milk (#70166, Lot. #BCB68664V, Fluka, UK) in TBS-T (0.1% Tween-20 SigmaUltra - P7949, Sigma-Aldrich, UK - in 1X Tris-buffer - #170-6435) for 1 hour at room temperature. Membranes were then cut into two sections and incubated with 1:1000 dilution in TBS-T mouse anti-human CD44 (Clone 156-3C11, #170-5061; Cell Signaling Technology, UK) overnight at 4°C, or 1:5000 dilution in TBS-T rabbit anti-human β-actin (ab8227, Abcam, UK) for 1 hour at room temperature. After four washings in TBS-T (15 min/wash under gentle agitation), membranes were incubated for 1 hour at room temperature with goat anti-mouse IgG-peroxidase (A0168, Sigma-Aldrich, UK) or goat anti-rabbit IgG-peroxidase (A0545, Sigma-Aldrich, UK), respectively. Bands were detected using Clarity Western enhanced chemiluminescence (ECL) substrate (#170-5061) with the aid of a ChemiDoc? MP System (#170-8280). ImageJ software (v1.49p, ) was used to perform a densitometry analysis of protein bands. Unless specified, all the products herein mention were purchased from Bio-Rad, UK.4.5. Cytokine profilingThe Ready-SET-Go! ELISA kits for Human TNF-α (#88-7346-88), Human IL-1β (2nd Generation, #88-7261-88), Human IL-10 (#88-7106-88), Human TGF-β1 (2nd Generation, #88-8350-88), and Corning? Costar flat-bottom ELISA plates used in this study were all purchased from Affymetrix/eBioscience (UK) and used according to manufacturer’s protocols.4.6. Cell imagingA) Light Microscopy. Phase contrast images of live THP-1 macrophages were acquired using a Leica DMI6000B inverted microscope (Leica Microsystems, UK) coupled with a 5.5 Neo sCMOS camera (Andor, UK). The μManager software (v.1.46, Vale Lab, UCSF, USA) was used to control both microscope and camera, as well as for image acquisition. For acquisitions, a dry 63X objective (NA=0.7, Leica Microsystems, UK) was used. Images were processed using ImageJ (v1.49p, ). B) Laser Scanning Confocal Microscopy (LSCM). An inverted SP5 laser confocal microscope (Leica TCS SP5 AOBS, Leica Microsystem, UK) was used to acquire volumetric datasets of resting and polarised THP-1 macrophages. Confocal acquisitions were performed using the immersion oil 63X/1.40 HCX PL Apo objective. THP-1 morphology and CD44 staining: THP-1 macrophages were stained for F-actin and nuclei after each differentiation procedure. Briefly, cells were incubated for 10 min with 1 μg/mL Hoechst (Invitrogen, Thermo-Fisher, UK) solution in serum-free medium at 37°C and 5% (v/v) CO2, cells were washed with PBS, fixed with 4% PFA solution for 10 min at room temperature, washed again with PBS, and then permeabilized with 0.1% (v/v) TritonX-100 solution in PBS (3 min incubation at room temperature). Cells were finally incubated for 20 min at room temperature with 1:200 Phalloidin-AlexaFluor488 (Invitrogen, Thermo-Fisher, UK) in 1% BSA (w/v) PBS solution, then washed with PBS, and stored in the dark at 4°C in a 1 mg/mL ascorbic acid solution in PBS. Images of polarized THP-1 macrophages were acquired using an inverted confocal laser microscope (Leica SP5). Volumetric dataset of differentiated and polarized THP-1 with both [24]/[6/18] and [24]*/[24/24] protocols were analyzed using ImageJ (v1.49p, ). The morphological analysis was performed considering the F-actin channel on volumetric datasets (n=2) observing about 10 cells per phenotype/method. Cell thickness was measured considering the difference between basal and the apical z-level. The measured difference was then multiplied by the z-size of the dataset voxel, obtaining the average thickness of each acquired cells. Cell surface area and solidity were measured using dataset maximum projections, Otsu threshold and watershed method were applied respectively to select cell bodies and to separate cell projections. Finally the surface area and the shape descriptors were determined using ImageJ plug-ins. Here, we present only solidity as the most representative descriptor to distinguish the macrophages phenotype/method.For CD44 staining, after incubation with 1 μg/mL Hoechst solution the cells were washed with cold PBS and placed on ice. A 1:200 dilution of anti-human CD44-Alexa594 conjugated antibody (#103054, Biolegend) in 1% (w/v) BSA/PBS was freshly prepared, incubating cells for 30 minutes on ice. Cells were then washed with PBS and fixed with 4% PFA solution incubating 10 minutes on ice. After permeabilization with 0.1% (v/v) Triton X-100 solution in PBS (3 min incubation at room temperature), cells were finally incubated for 20 min at room temperature with a 1:200 Phalloidin-AlexaFluor488 (Invitrogen, Thermo-Fisher, UK) in 1% (w/v) BSA/PBS solution, washed with PBS and stored in the dark at 4°C in a 1 mg/mL ascorbic acid solution (PBS).HA internalization. Sections and high-resolution (3D-HR) volumetric dataset were also acquired to precisely determine HA-Rho localization within the cell. For 3D-HR acquisitions, the confocal settings were set as follows: 1 Airy unit, scan speed 700 Hz, Average Line ×2, pixel size 117 nm, 0.4 ?m z-step. To get rid of any possible cross talk between channels, images were collected with a sequential scan, using the following laser lines and mirror settings: 405(10%)/410-460 nm; 488(30%)/500-550 nm; 561(25%)/575-680 nm. Sections were then processed and analyzed using ImageJ, accordingly to the acquisition analysis. 3D rendering was performed using Imaris x64 (v7.7.2, Bitplane AG). Before acquisitions, the bottom and the top level were determined using the F-actin signal. At a post-processing level, the following morphological parameters were calculated:- Approximated cell thickness, determined as the average basal vs. apical plane distance for each cell.- Average surface area, determined with the maximum projection result of the volumetric dataset.- Solidity of cell surface, determined after applying threshold method and calculating shape descriptors of the maximum projection (derived from volumetric dataset).4.7. Preparation of fluorescently-labelled HA (HA-Rho)Hyaluronic acid (HA; Mw = 180 kDa, assessed by GPC as described in Supporting Information, section SI5 and Table 1SI) was provided by Novozymes (Bagsvaerd, Denmark) and covalently conjugated to Lissamine? Rhodamine B Ethylenediamine (Thermo Scientific, UK). All solutions were prepared in 100 mM HEPES buffer at pH = 7.4 unless stated otherwise. Briefly, 150 mg of HA (0.5 mmol of carboxylate) were dissolved in 15 mL by shaking overnight. After complete dissolution of HA, 3.75 mL of a solution containing 4.32 mg of Rhodamine were added followed by 3.75 mL of 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM) (Sigma-Aldrich, UK). The reaction was stirred (at 300 rpm) for 24 h at 25°C and then quenched and precipitated using a 20-fold volume excess of ethanol (96% v/v). The mixture was further incubated overnight at 4°C to ensure the complete precipitation of the labelled HA. The precipitate was collected after centrifugation (10 min at 4500 g), dissolved in 15 mL of deionised water, and purified by dialysis (MW cut-off?20 kDa). Finally, the HA solution was freeze-dried. Mass recovery: 74%. Degree of derivatization: 0.7% mol (calculated by measuring the fluorescence of Rhodamine-conjugated HA (Ex: 540/25, Em: 620/40 nm) and comparing it to a calibration with free Rhodamine).4.8. Preparation of HA-coated chitosan nanoparticles (CS/HA)Chemicals. Middle viscosity chitosan (CS, average viscosimetric molecular weight Mv= 656 kDa) and degree of deacetylation 85%) was purchased from Sigma (Sigma-Aldrich, UK). Chitosan with Mv= 36 kDa was obtained by oxidative degradation of middle viscosity chitosan (1% wt. in 0.1 M HCl / 3 mM sodium nitrite). Chitosan samples were purified in-house prior to use as previously described ADDIN EN.CITE <EndNote><Cite><Author>Gennari</Author><Year>2016</Year><RecNum>87</RecNum><DisplayText><style face="superscript">[56]</style></DisplayText><record><rec-number>87</rec-number><foreign-keys><key app="EN" db-id="zfewd20tk9d0ates5eypzaddvveafdwptpwr" timestamp="1471357511">87</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Gennari, A.</author><author>Pelliccia, M.</author><author>Donno, R.</author><author>Kimber, I.</author><author>Tirelli, N.</author></authors></contributors><titles><title>Mannosylation Allows for Synergic (CD44/C-Type Lectin) Uptake of Hyaluronic Acid Nanoparticles in Dendritic Cells, but Only upon Correct Ligand Presentation</title><secondary-title>Advanced Healthcare Materials</secondary-title></titles><periodical><full-title>Advanced Healthcare Materials</full-title><abbr-1>Adv Healthc Mater</abbr-1></periodical><pages>966-976</pages><volume>5</volume><number>8</number><dates><year>2016</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>2192-2640</isbn><accession-num>WOS:000374693700013</accession-num><urls><related-urls><url>&lt;Go to ISI&gt;://WOS:000374693700013</url></related-urls></urls><electronic-resource-num>10.1002/adhm.201500941</electronic-resource-num></record></Cite></EndNote>[56]. Nanoparticle preparation. Nanoparticles were prepared by direct complexation of chitosan (CS) with HA and siRNA, following a single-step method recently adopted in our group; please note that this is not the two-stage triphosphate (TPP)-mediated process previously employed by usPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BbG1hbGlrPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

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ADDIN EN.CITE.DATA [21, 56]. This simplified approach encompasses first the preparation of a 0.069% wt. CS solution (36 or 656 kDa) in 4.6 mM HCl, the pH of the solution was then adjusted to 5 by adding 0.1 mM NaOH. The latter was further diluted 1:2 (v/v) with deionised water brought to pH = 5 using HCl 0.1 M; in the case of loaded nanoparticles, the CS solution was diluted with deionised nuclease-free water containing DY547-labelled siRNA (1.45%wt. in relation to CS) (Dharmacon, UK) and an initial complexation was carried under magnetic agitation (1,000 rpm) for 10 min at 25°C. The HA-coated nanoparticles (CS/HA) were obtained by addition of the resulting CS solution/suspension into an equal volume of a 1.5 mg/mL HA solution (HA-Rho for empty nanoparticles; non-labelled HA for the siRNA-loaded ones) in water at pH = 5 under vigorous stirring (1,000 rpm) for 30 min at 25°C. Please note that the preparation of nanoparticles was performed in a laminar flow hood with surfaces previously decontaminated using the RNaseZap? solution (Thermo Scientific, UK) when encapsulating siRNA payloads. Size and ?-potential of the particles are reported in Supporting Information, section SI5 and Table 1SI.4.9. Study of macrophage-HA interactionsIn the following paragraphs, we will refer to soluble HA or CS/HA nanoparticles as “treatment”. Briefly, equal volumes of soluble HA or CS/HA nanoparticles (adjusted to 250 ?g/mL with deionised water) were diluted with 2X concentrated RPMI 1640 medium to obtain a final concentration of 125 ?g/mL in complete cell culture medium. Please note that internalization studies (flow cytometry) of soluble HA were performed by tracking the HA-Rho signal, while those of CS/HA nanoparticles were performed by tracking an encapsulated fluorescently-labelled siRNA, respectively (see previous section for the preparation procedure).A) Quantification of HA binding and uptake in cell lysates. THP-1 premonocytes were differentiated and polarized in Costar? polystyrene 12-well plates with flat bottom (3513; Corning, UK). Cells were incubated with the treatment at 37°C. After specified incubation times (0, 2, 4, 8, 16, and 24 h), cells were washed three times with pre-warmed PBS and lysed in 100 μL RIPA Buffer. The total uptake (comprising both membrane-bound and internalized macromolecules) was estimated from the measured fluorescence of the cell lysates, by using a calibration of HA-Rho or CS/HA nanoparticles in cell lysates at concentration range [0.12-125]?g/mL (Ex: 540/25, Em: 620/40 nm) Synergy2 Biotek plate reader using Gen5 software. Sensitivity adjusted to the highest HA-Rho or CS/HA nanoparticles concentration of the calibration curve (125 ?g/mL). Optical position: top 50%. Light source: Xenon flash) and normalized against the protein content in each well, as analysed via the BCA assay kit (B9643, Sigma-Aldrich, UK). B) Quantification of HA internalization via flow cytometry. THP-1 premonocytes were differentiated and polarized in Costar? polystyrene 6-well plates (3513; Corning, UK). Cells were incubated with the treatment at 37°C. After specified incubation times (0, 2, 4, 8, 16, and 24 h), cells were washed three times with pre-warmed PBS to remove any excess. Macrophages were then detached using pre-warmed Cell Dissociation Buffer (#13151-014, Gibco?/Invitrogen, UK) with 15 minutes incubation at RT. The internalization was determined on 10,000 live, individual cells with a BD LSRFortessa cytometer (BD Bioscience, San Jose CA, USA) equipped with the FACSDiva software (v8.0.1). Data were analyzed with FlowJo (vX.0.7, Tree Star, Ashland, OR, USA) after gating live and single events in the FSC-A/FSC-H (singlets) and FSC/SSC (live) windows, respectively. Untreated cells were used as autofluorescence control in order to calculate the MFI for each time point, as well as the percentage of positive events. C) CD44 blocking. THP-1 premonocytes were differentiated and polarized in Costar? polystyrene 12-well plates with flat bottom (3513; Corning, UK). Macrophages were pre-treated with RPMI 1640 medium containing either i) 20 μg/mL CD44 antibody (Clone HERMES-I; MA4400, Fischer Scientific UK), or ii) 20 μg/mL Rat IgG2a antibody (MCA1212, Ad Serotec), or iii) PBS for 1h at 37°C. Pre-treatment was followed by incubation with RPMI 1640 medium containing HA-Rho (125 μg/mL) together with either i) 10 μg/mL CD44 antibody, or ii) 10 μg/mL IgG2a, or iii) PBS for 2h at 37°C. Media were removed and cells were washed three times in pre-warmed PBS and lysed in 100 μL RIPA buffer. The total HA uptake (comprising both membrane-bound and internalized macromolecules) was estimated D) HA intracellular localisation (via LSCM). THP-1 premonocytes were differentiated and polarized in the ?-Slide 8-well slide (iBiDi, UK). Cells were incubated with a 125 ?g/mL HA-Rho solution in complete RPMI 1640 at 37°C. After 16 h incubation, cells were washed with PBS and fixed with a 4% PFA solution (5 min at RT). Cells were then washed with cold PBS (n=3), incubated for 10 min at RT with a 1% FBS solution in PBS, washed with PBS (n=3), incubated for 30 min at RT with 1:400 human anti-CD44 (156-3C11, Cell Signaling) in PBS, 1% (w/v) BSA, washed with PBS (n=3), and finally incubated for another 30 min at RT with anti-mouse IgG (whole molecule)–FITC antibody produced in goat (F0257, Sigma-Aldrich, UK) in PBS, 1% (w/v) BSA. Finally, cells were incubated for 3 min at RT with a 1 ?g/mL DAPI solution in PBS, washed with PBS (n=3), and stored in the dark at 4°C in a 0.1 mg/mL ascorbic acid (A4403, Sigma-Aldrich, UK) solution in PBS. 4.10. Statistical analysis. The expression of markers and cytokines was compared using a two-way analysis of variance (Two-way ANOVA), setting the macrophage phenotype (i.e. M0, M1 or M2) as row factor and the differentiation/polarization method as column factor. In experiments related to CD44 isoforms and CD44-mediated uptake inhibition, we compared results between different phenotypes using one-way analysis of variance (One-way ANOVA). Differences between groups were considered significant at a P value of <0.05. Statistical analysis performed with GraphPad Prism 6.04 (GraphPad Software, Inc., San Diego, CA).Supporting InformationSupporting information is available from the Wiley Online LibraryAcknowledgementsNovozymes Biopharma (Krogshoejvej 36, 2880 36, 2880 Bagsvaerd, Denmark) is gratefully acknowledged for the provision of hyaluronic acid. The authors also want to thank Prof. Tony Day (University of Manchester) for the helpful discussions.This study was supported by EPSRC (PhD studentship for Mr. Rios de la Rosa as part of the North-West Nanoscience (NoWNano) Doctoral Training Centre, EPSRC grant EP/G03737X/1). 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