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Inflammatory Arthritis Negatively Regulates Mouse Α PILR PILRα Negatively Regulates Mouse Inflammatory Arthritis Yonglian Sun, Patrick Caplazi, Juan Zhang, Anita Mazloom, Sarah Kummerfeld, Gabriel Quinones, Kate Senger, Justin This information is current as Lesch, Ivan Peng, Andrew Sebrell, Wilman Luk, Yanmei of September 25, 2021. Lu, Zhonghua Lin, Kai Barck, Judy Young, Mariela Del Rio, Sophie Lehar, Vida Asghari, WeiYu Lin, Sanjeev Mariathasan, Jason DeVoss, Shahram Misaghi, Mercedesz Balazs, Tao Sai, Benjamin Haley, Philip E. Hass, Min Xu, Wenjun Ouyang, Flavius Martin, Wyne P. Lee and Ali A. Downloaded from Zarrin J Immunol 2014; 193:860-870; Prepublished online 16 June 2014; doi: 10.4049/jimmunol.1400045 http://www.jimmunol.org/content/193/2/860 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2014/06/16/jimmunol.140004 Material 5.DCSupplemental References This article cites 43 articles, 15 of which you can access for free at: http://www.jimmunol.org/content/193/2/860.full#ref-list-1 by guest on September 25, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology PILRa Negatively Regulates Mouse Inflammatory Arthritis Yonglian Sun,* Patrick Caplazi,† Juan Zhang,* Anita Mazloom,‡ Sarah Kummerfeld,x Gabriel Quinones,‡ Kate Senger,* Justin Lesch,* Ivan Peng,* Andrew Sebrell,{ Wilman Luk,‖ Yanmei Lu,‖ Zhonghua Lin,* Kai Barck,# Judy Young,‖ Mariela Del Rio,** Sophie Lehar,†† Vida Asghari,** WeiYu Lin,* Sanjeev Mariathasan,†† Jason DeVoss,* Shahram Misaghi,‡‡ Mercedesz Balazs,* Tao Sai,{ Benjamin Haley,‡ Philip E. Hass,‡ Min Xu,* Wenjun Ouyang,* Flavius Martin,* Wyne P. Lee,* and Ali A. Zarrin* Paired Ig-like type 2 receptor (PILR)a inhibitory receptor and its counterpart PILRb activating receptor are coexpressed on myeloid cells. In this article, we report that PILRa, but not PILRb, is elevated in human rheumatoid arthritis synovial tissue and correlates with inflammatory cell infiltration. Pilra2/2 mice produce more pathogenic cytokines during inflammation and are Downloaded from prone to enhanced autoimmune arthritis. Correspondingly, engaging PILRa with anti-PILRa mAb ameliorates inflammation in mouse arthritis models and suppresses the production of proinflammatory cytokines. Our studies suggest that PILRa mediates an important inhibitory pathway that can dampen inflammatory responses. The Journal of Immunology, 2014, 193: 860–870. mmune responses are modulated by a network of positive- ITAM-bearing DAP12 adaptor molecule to deliver activating si- and negative-regulatory mechanisms. Paired receptors consist gnals (8). Human and mouse PILRa share only ∼40% homology http://www.jimmunol.org/ I of highly related activating and inhibitory receptors that (7), yet conserved residues mediate ligand interactions (9). are widely involved in the regulation of the immune system (1). PILRa and PILRb transcripts show similar tissue expression, Both inhibitory and activating receptors share high similarity with high levels in spleen, liver, and lung and lower levels in in their extracellular domain, whereas their intracellular signal- the small intestine (8). PILRa and PILRb are predominantly ing domains are divergent (2, 3). Paired Ig-like type 2 receptor expressed in cells of the myelomonocytic lineage, including (PILR)a belongs to the Ig superfamily. Its intracellular domain monocytes, macrophages, granulocytes, and monocyte-derived contains two ITIMs that recruit SHP-1 and SHP-2 to trigger an dendritic cells (DCs) (4, 8). Additionally, PILRb is expressed in inhibitory signaling cascade, resulting in reduced intracellular NK cells (8). It was shown that PILRa binds to mouse CD99 (8), calcium mobilization (4, 5). PILRa and its gene-linked activating PILR-associating neural protein (10), and HSV-1 glycoprotein B by guest on September 25, 2021 counterpart, PILRb, share highly similar extracellular domains, (11). Specific sialylated O-linked glycans on ligands are required suggesting that they may recognize the same ligands (5–7). PILRb for their binding to PILRa (6, 10, 12). We recently identified two has a truncated cytoplasmic domain and a charged amino acid more binding partners of PILRa, neural proliferation differentia- residue in its transmembrane region that associates with the tion and control-1 and collectin-12, and found that an evolution- arily conserved PILRa domain mediates its interaction with these diverse sialylated ligands (9). This suggests that a complex net- *Department of Immunology, Genentech, South San Francisco, CA 94080; work of ligands might modulate cellular functions via PILRa.It †Department of Pathology, Genentech, South San Francisco, CA 94080; was shown that PILRa binds to HSV-1 glycoprotein B and serves ‡Department of Protein Chemistry, Genentech, South San Francisco, CA 94080; x as a virus entry coreceptor (11, 13). Previous studies showed that Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080; {Department of Antibody Engineering, Genentech, South San PILRb-deficient and agonist anti-PILRa–treated mice show im- ‖ Francisco, CA 94080; Department of Biochemical and Cellular Pharmacology, Gen- proved clearance of infectious reagents and improved survival (14, entech, South San Francisco, CA 94080; #Department of Biomedical Imaging, Gen- entech, South San Francisco, CA 94080; **Department of Transgenic Technology, 15). A recent study showed that PILRa negatively regulates Genentech, South San Francisco, CA 94080; ††Department of Microbial Pathogen- neutrophil recruitment during TLR-mediated inflammatory responses ‡‡ esis, Genentech, South San Francisco, CA 94080; and Department of Early Stage (16). However, the role of PILRa or PILRb in autoimmunity is Cell Culture, Genentech, South San Francisco, CA 94080 largely unknown. Received for publication January 9, 2014. Accepted for publication May 19, 2014. Myeloid cells play a critical role in the pathophysiology of The microarray data presented in this article have been submitted to the National inflammation and autoimmunity. Rheumatoid arthritis (RA) is Center for Biotechnology Information’s Gene Expression Omnibus (http://www.ncbi. nlm.nih.gov/geo/query/acc.cgi?acc=GSE48780) under accession number GSE48780. a systemic, inflammatory, autoimmune disorder manifested by Address correspondence and reprint requests to Dr. Ali A. Zarrin, Genentech, 1 DNA chronic polyarthritis with synovial hyperplasia and joint destruc- Way, South San Francisco, CA 94080. E-mail address: [email protected] tion, resulting in pain, loss of joint function, and concomitant The online version of this article contains supplemental material. reduction of life quality (17, 18). Myeloid cells, including Abbreviations used in this article: BM, bone marrow; BMDC, BM-derived DC; monocytes/macrophages and neutrophils, play an important role BMDM, BM-derived monocyte; CAIA, collagen Ab–induced arthritis; CLEC4G, in various stages of arthritis development (19, 20). To investigate C-type lectin domain family 4, member G; DC, dendritic cell; ES, embryonic stem; h, human; JCBV, joint cortical bone volume; m, mouse; micro-CT, microcomputed the role of PILRa in myeloid cell–mediated immune responses tomography; MPO, myeloperoxidase; OA, osteoarthritis; PILR, paired Ig-like type 2 and its effects on autoimmune diseases, we studied its function receptor; PNBV, periosteal new bone volume; RA, rheumatoid arthritis; WT, wild- in myeloid-driven models of RA, including collagen Ab–induced type. arthritis (CAIA) and K/BxN serum–transfer arthritis, using PILRa- Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 deficient mice and PILRa-specific mAbs. Murine CAIA is in- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400045 The Journal of Immunology 861 duced by i.v. injection of mAbs against type II collagen, fol- mAbswasconfirmedbyELISAandflowcytometryanalysis.ThesemAbsdo lowedbyi.p.injectionofLPS.Thismodeliswidelyusedto not cross-react with mouse PILRb. Hamster anti-PILRa mAb was used for study the pathogenesis of autoimmune arthritis and to determine staining, and mouse anti-PILRa mAb was used for in vivo and in vitro functional studies. efficacy of therapeutics (21–24). Myeloid cells, FcgRs (22), and proinflammatory cytokines, especially TNF-a and IL-1b (21), are Gene expression analysis indispensable for the development and maintenance of arthritis in For gene expression analysis, total RNA was isolated using TRIzol reagent this model (23). The K/BxN serum–transfer arthritis model is (Invitrogen). Total RNA (50 ng) was subjected to RT-PCR using Access RT- induced by transferring K/BxN serum into normal mice; LPS is PCR System (Promega). Primers used for amplification were as follows: not needed in this model. The K/BxN serum–transfer arthritis b-actin,
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