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CD44 Antibody Inhibition of Macrophage Phagocytosis Targets Fcγ Receptor

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CD44 Antibody Inhibition of Macrophage Phagocytosis Targets Fcγ Receptor Published March 4, 2016, doi:10.4049/jimmunol.1502198 The Journal of Immunology CD44 Antibody Inhibition of Macrophage Phagocytosis Targets Fcg Receptor– and Complement Receptor 3–Dependent Mechanisms Alaa Amash,*,† Lin Wang,‡ Yawen Wang,‡ Varsha Bhakta,x Gregory D. Fairn,† Ming Hou,‡ Jun Peng,‡ William P. Sheffield,*,x and Alan H. Lazarus*,†,{ Targeting CD44, a major leukocyte adhesion molecule, using specific Abs has been shown beneficial in several models of autoim- mune and inflammatory diseases. The mechanisms contributing to the anti-inflammatory effects of CD44 Abs, however, remain poorly understood. Phagocytosis is a key component of immune system function and can play a pivotal role in autoimmune states where CD44 Abs have shown to be effective. In this study, we show that the well-known anti-inflammatory CD44 Ab IM7 can inhibit murine macrophage phagocytosis of RBCs. We assessed three selected macrophage phagocytic receptor systems: Fcg receptors (FcgRs), complement receptor 3 (CR3), and dectin-1. Treatment of macrophages with IM7 resulted in significant inhibition of FcgR-mediated phagocytosis of IgG-opsonized RBCs. The inhibition of FcgR-mediated phagocytosis was at an early stage in the phagocytic process involving both inhibition of the binding of the target RBC to the macrophages and postbinding events. This CD44 Ab also inhibited CR3-mediated phagocytosis of C3bi-opsonized RBCs, but it did not affect the phagocytosis of zymosan particles, known to be mediated by the C-type lectin dectin-1. Other CD44 Abs known to have less broad anti-inflammatory activity, including KM114, KM81, and KM201, did not inhibit FcgR-mediated phagocytosis of RBCs. Taken together, these findings demonstrate selective inhibition of FcgR and CR3-mediated phagocytosis by IM7 and suggest that this broadly anti- inflammatory CD44 Ab inhibits these selected macrophage phagocytic pathways. The understanding of the immune-regulatory effects of CD44 Abs is important in the development and optimization of therapeutic strategies for the potential treatment of autoimmune conditions. The Journal of Immunology, 2016, 196: 000–000. he CD44 transmembrane glycoprotein is one of the most glycoproteins (80–200 kDa in size) is encoded by a single, highly structurally and functionally variable surface molecules conserved gene (2). The wide molecular diversity is in part gen- T present on most nucleated cells (1). The CD44 group of erated by alternative splicing, which affects predominantly the extracellular domains of the protein, and by posttranslational modifications, which differ depending on the cell type and growth *Canadian Blood Services Centre for Innovation, Toronto, Ontario K1G 4J5, Canada; conditions (3). The standard or hematopoietic isoform (CD44s) is †Keenan Research Centre for Biomedical Science, Li Ka Shing Knowledge Institute, present on the membrane of most vertebrate cells (4). In addition ‡ St. Michael’s Hospital, Toronto, Ontario M5B 1T8, Canada; Department of Hema- to its role in hyaluronic acid (HA) binding, numerous studies tology, Qilu Hospital, Shandong University, Jinan, Shandong 250012, China; xDepartment of Pathology and Molecular Medicine, McMaster University, Hamilton, suggest that CD44 may modulate immune responses and inflam- { Ontario L8N 3Z5, Canada; and Department of Laboratory Medicine and Patho- mation through at least two major mechanisms. First, CD44 was biology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A1, Canada shown to play an important role in controlling leukocyte extrav- asation and infiltration into inflammatory sites (5–7). Second, ORCIDs: 0000-0001-8922-8826 (L.W.); 0000-0003-4876-1207 (Y.W.); 0000-0001- 6508-168X (G.D.F.); 0000-0002-5870-8189 (W.P.S.). CD44 can induce signal transduction pathways and cell activation. Received for publication October 13, 2015. Accepted for publication February 8, Engagement of CD44 was shown to trigger cytotoxic function in 2016. T cells, and CD44 expression correlates positively with regulatory This work was supported by peer-reviewed operating grants from the Canadian Blood T cell potency and function (8–10). Additionally, association be- Services/Canadian Institutes of Health Research Partnership to A.H.L. (Grant tween CD44 deficiency and enhanced proinflammatory cytokine FRN6897) and from the Canadian Blood Services Intramural Operating Grant pro- gram to A.H.L. (Grant 2013-IG-AL00545). Resources for both programs are pro- production by peritoneal macrophages in response to Escherichia vided by Health Canada, a division of the federal government of Canada. A.A. is the coli was recently reported (11). Recent studies suggest a possible recipient of a Canadian Blood Services postdoctoral fellowship. The views expressed role for CD44 in negative regulation of TLR-mediated inflam- herein do not necessarily represent the views of the federal government of Canada. matory responses (12, 13). Address correspondence and reprint requests to Dr. Alan H. Lazarus, Keenan Re- search Centre for Biomedical Science, St. Michael’s Hospital, 209 Victoria Street, Phagocytosis is a critical component of both innate and adaptive Toronto, ON M5B 1T8, Canada. E-mail address: [email protected] immunity and can play key roles in the first line of defense against The online version of this article contains supplemental material. invading microorganisms as well as in tissue homeostasis and Abbreviations used in this article: BMDM, bone marrow–derived macrophage; C3bi- remodeling (14). Dysregulation of phagocytosis can lead not only SRBC, C3bi-opsonized SRBC; CMFDA, 5-chloromethylfluorescein diacetate; com- to impaired host immune responses to pathogens, but may also plete RPMI, RPMI 1640, 10% FBS, 4 mM L-glutamine, penicillin (100 U/ml), and streptomycin (100 mg/ml); CR3, complement receptor 3; FcgR, Fcg receptor; HA, lead to alterations in immune tolerance and to the development of hyaluronic acid; IgG-SRBC, IgG-opsonized SRBC; ITP, immune thrombocytopenia; chronic inflammation and autoimmunity (15). The phagocytic PerM, peritoneal macrophage; PFA, paraformaldehyde; PNGase, peptide-N-glycosi- process can be initiated by a wide range of surface receptors dase; RAW, RAW264.7. which often involve two main groups: nonopsonic receptors that Copyright Ó 2016 by The American Association of Immunologists, Inc. 0022-1767/16/$30.00 are capable of direct recognition and binding of target particles, www.jimmunol.org/cgi/doi/10.4049/jimmunol.1502198 2 REGULATION OF MACROPHAGE PHAGOCYTOSIS BY ANTI-CD44 and opsonic receptors that recognize opsonins, such as Abs and marrow–derived macrophages (BMDM) from C57BL/6- and CD44- complement. Of these opsonic receptors, Fcg receptors (FcgRs), deficient mice were generated as previously described by Zhang et al. which bind the Fc portion of IgG, and complement receptor 3 (36). Peritoneal macrophages (PerM) were prepared by injection of cold RPMI 1640 into the peritoneum of euthanized CD1 female mice, followed (CR3), which binds the C3bi component of complement, are the by rapid removal of all fluid. The peritoneal cells obtained were washed best described (16). For the nonopsonic receptors, dectin-1 is the with cold PBS and resuspended in complete RPMI. Cells were cultured in most studied receptor and is thought to be the major receptor for Nunclon surface cell culture dishes (Nunc, Roskilde, Denmark) at 37˚C the fungal cell wall component b-glucan in macrophages (17). and 5% CO2 for 4 h, followed by extensive washing with cold PBS to remove nonadherent cells. Adherent cells were removed with a scraper and Abs to CD44 have been successfully used in the treatment of transferred to complete RPMI, counted, and cultured in flat-bottom 12-well several animal models of autoimmune and inflammatory diseases, tissue culture plates (Corning, Corning, NY) at 5 3 105 cells/well at 37˚C including experimental autoimmune encephalomyelitis (18, 19), and 5% CO2 overnight. Cells were then washed and incubated in complete collagen- or Ab-induced arthritis (7, 20–23), autoimmune diabetes RPMI for the analysis of phagocytosis. The purity of the PerM population . (24, 25), experimental autoimmune uveoretinitis (26, 27), exper- following this procedure was 90% as determined by flow cytometry using fluorescently labeled anti-CD45 and anti-F4/80 Abs (data not imental colitis (28), experimental pulmonary eosinophilia (29), shown). and cutaneous delayed-type hypersensitivity (30). The mAb rat For use in FcgR- or CR3-mediated phagocytosis assays, RAW cells, anti-human/mouse CD44, IM7, which recognizes an extracellular BMDM, or PerM were cultured at 5 3 105/well overnight in 12-well tissue epitope on the CD44s, has been extensively used in many of these culture plates. For zymosan phagocytosis, RAW macrophages were cul- tured at 105/well overnight in 24-well plates. studies, and robust anti-inflammatory effects have been reported with the administration of the Ab in these disease models (7, 18, FcgR-mediated phagocytosis 19, 21, 22, 24–26). In comparison, the mAbs KM81, KM201, and KM114 have only been shown to have limited anti- SRBCs (MP Biomedicals) were washed with PBS, resuspended at 5 3 108/ml inflammatory activity in arthritis (20–23). In addition to the in PBS, and opsonized with a subagglutinating concentration (50 mg/ml) of polyclonal rabbit anti-SRBC IgG for 1 h at room temperature with broad anti-inflammatory effects of IM7, it is also been demon- gentle agitation, followed by washing with PBS to remove the unbound strated to inhibit hematopoiesis as well as homing of bone Ab. Subsequent
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