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CD31 Acts As a Checkpoint Molecule and Is Modulated by Fcγr-Mediated Signaling in Monocytes

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CD31 Acts As a Checkpoint Molecule and Is Modulated by Fcγr-Mediated Signaling in Monocytes CD31 Acts as a Checkpoint Molecule and Is Modulated by Fc γR-Mediated Signaling in Monocytes This information is current as Giovanna Merchand-Reyes, Frank H. Robledo-Avila, of September 28, 2021. Nathaniel J. Buteyn, Shalini Gautam, Ramasamy Santhanam, Kavin Fatehchand, Xiaokui Mo, Santiago Partida-Sanchez, Jonathan P. Butchar and Susheela Tridandapani J Immunol published online 15 November 2019 Downloaded from http://www.jimmunol.org/content/early/2019/11/14/jimmun ol.1900059 Supplementary http://www.jimmunol.org/content/suppl/2019/11/15/jimmunol.190005 http://www.jimmunol.org/ Material 9.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 28, 2021 • 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 © 2019 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published November 15, 2019, doi:10.4049/jimmunol.1900059 The Journal of Immunology CD31 Acts as a Checkpoint Molecule and Is Modulated by FcgR-Mediated Signaling in Monocytes Giovanna Merchand-Reyes,* Frank H. Robledo-Avila,† Nathaniel J. Buteyn,* Shalini Gautam,* Ramasamy Santhanam,* Kavin Fatehchand,* Xiaokui Mo,‡ Santiago Partida-Sanchez,‡ Jonathan P. Butchar,* and Susheela Tridandapani* Monocytes and macrophages express FcgR that engage IgG immune complexes such as Ab-opsonized pathogens or cancer cells to destroy them by various mechanisms, including phagocytosis. FcgR-mediated phagocytosis is regulated by the concerted actions of activating FcgR and inhibitory receptors, such as FcgRIIb and SIRPa. In this study, we report that another ITIM-containing receptor, PECAM1/CD31, regulates FcgR function and is itself regulated by FcgR activation. First, quantitative RT-PCR and flow cytometry analyses revealed that human monocyte FcgR activation leads to a significant downregulation of CD31 expression, both at the message level and at surface expression, mainly mediated through FcgRIIa. Interestingly, the kinetics of downregulation Downloaded from between the two varied, with surface expression reducing earlier than the message. Experiments to analyze the mechanism behind this discrepancy revealed that the loss of surface expression was because of internalization, which depended predominantly on the PI3 kinase pathway and was independent of FcgR internalization. Finally, functional analyses showed that the downregulation of CD31 expression in monocytes by small interfering RNA enhanced FcgR-mediated phagocytic ability but have little effect on cytokine production. Together, these results suggest that CD31 acts as a checkpoint receptor that could be targeted to enhance FcgR functions in Ab-mediated therapies. The Journal of Immunology, 2019, 203: 000–000. http://www.jimmunol.org/ ngagement of Ab-coated targets by macrophages and and sends a “don’t eat me” signal, has been reported to downregulate monocytes occurs primarily through FcgR. In humans, FcgR-mediated phagocytosis (4, 5). E FcgRIa, -IIa, and -IIIa initiate positive signals through an Monocyte FcgR functions play a critical role in Ab-based ITAM (1). ITAM phosphorylation activates signaling pathways, therapies for diseases such as cancer (6). Hence, the full effi- such as the PI3K and MAPK cascades. This results in functional cacy of such treatment requires robust FcgR function. In this responses, including phagocytosis, cytokine release, generation of context, the identification of negative regulatory/checkpoint reactive oxygen species, and Ab-dependent cellular cytotoxicity receptors that dampen such function provides an avenue for by guest on September 28, 2021 (2). Conversely, FcgRIIb acts as a negative regulator through its enhancing the efficacy of response by targeting these receptors. ITIM. When phosphorylated, this ITIM recruits phosphatases, In this study, we report another checkpoint receptor that reg- such as the SH2 domain containing inositol phosphatase. These ulates monocyte FcgR function. dampen FcgR-mediated responses (3). PECAM-1/CD31, discovered primarily as an adhesion molecule In addition to FcgRIIb, the ITIM-containing signal-regulatory that allows the transmigration of leukocytes from blood vessels to protein a (SIRPa), which binds to CD47 displayed by target cells the tissues (7), has been found to be expressed in the vascular endothelia as well as in T cells, B cells, dendritic cells (DCs), neutrophils, monocytes, and macrophages (8). CD31 is a member *Division of Hematology, Department of Internal Medicine, The Ohio State Univer- of the Ig gene superfamily that contains six extracellular domains, † sity College of Medicine, Columbus, OH 43210; Center for Microbial Pathogenesis, an intermembrane domain, and a cytoplasmic tail that bears two The Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205; and ‡Center for Biostatistics, Department of Bioinformatics, The Ohio State University ITIMs capable of binding various molecules, including SHP1 and -2, College of Medicine, Columbus, OH 43210 SH2 domain containing inositol phosphatase 2, PI3K, and phos- ORCIDs: 0000-0002-2933-2493 (G.M.-R.); 0000-0001-5583-9194 (F.H.R.-A.); pholipase C-g1 (9, 10). Previous studies indicated that there is 0000-0002-3739-0247 (S.G.); 0000-0002-8471-1699 (R.S.); 0000-0003-0592- preferential binding to these signaling proteins depending on the 5494 (K.F.); 0000-0003-2996-9440 (S.P.-S.). cell type, such as SHP2 in T cells and SHP1 in DCs (11–13). As Received for publication January 17, 2019. Accepted for publication October 5, 2019. such, CD31 is implicated in diverse functions, including inhibition of Ab-mediated aggregation in platelets, inhibition of BCR acti- This work was supported by National Cancer Institute/National Institutes of Health R01CA203584 (to S.T. and J.P.B.), National Cancer Institute/National Institutes of vation, and reduction of proinflammatory DC maturation (13–15). Health R01CA162411 (to S.T. and J.P.B.), a Pelotonia Award (to S.T.), and Pelotonia Although CD31 has been broadly studied, its role in FcgR-mediated Fellowship (to G.M.-R.). responses in monocytes is poorly understood. Our studies demon- Address correspondence and reprint requests to Jonathan P. Butchar and Susheela strate that CD31 negatively regulates FcgR-mediated phagocytosis, Tridandapani, Division of Hematology, Department of Internal Medicine, The Ohio State University, 400 W. 12th Avenue, Columbus, OH 43210. E-mail addresses: as this activity was enhanced in monocytes following the knockdown [email protected] (J.P.B.) and [email protected] (S.T.) of CD31. In contrast, CD31 had little effect on cytokine produc- The online version of this article contains supplemental material. tion. We also show in this study that FcgR activation rapidly Abbreviations used in this article: DC, dendritic cell; DIgG, heat-aggregated IgG; PB, downregulates surface expression of CD31 and later reduces polymyxin B; PBM, peripheral blood monocyte; Scr, scrambled; siRNA, small CD31 transcript. This effect is mainly mediated through FcgRIIa interfering RNA; SIRPa, signal-regulatory protein a; WGA, wheat germ agglutinin. activity. Hence, we propose that CD31 represents a negative Copyright Ó 2019 by The American Association of Immunologists, Inc. 0022-1767/19/$37.50 regulatorofspecificFcgR activities that is itself regulated by www.jimmunol.org/cgi/doi/10.4049/jimmunol.1900059 2 CD31 IS A CHECKPOINT MOLECULE FOR FcgR FcgR. This regulatory loop may serve to enhance FcgR responses Abs: Anti-PECAM1, anti–phospho-cJun, anti–phospho-p42/44, anti– to Ab-coated targets. phospho-Akt (Ser473), anti–phospho-MAPK–APK2, c-Jun, Erk, Akt, MAPK–APK2, GAPDH (Cell Signaling Technology, Danvers, MA), CD32b (Abcam, Cambridge, MA), CD32a (Epitomics, Abcam, Cam- Materials and Methods bridge, MA), FcεRI g-chain (Upstate/MilliporeSigma, Burlington, MA), Peripheral blood monocyte isolation and stimulation or/and calreticulin (Enzo Life Sciences, Farmingdale, NY). Anti-mouse– HRP and anti-rabbit–HRP (Santa Cruz Biotechnology, Dallas, TX) were Peripheral blood monocytes (PBM) were isolated from healthy donor used as secondary Abs. Blots were developed using Pierce ECL Western leukopacks (Red Cross Blood Services, Columbus, OH) as previously Blotting Substrate or SuperSignal West Femto Maximum Sensitivity described (16). Briefly, whole blood was separated using lymphocyte Substrate (Thermo Fisher Scientific). Densitometry was done using separation medium (Corning, Corning, NY) through centrifugation. ImageJ software (National Institutes of Health, Bethesda, MD), nor- PBMCs were collected, washed with incomplete RPMI 1640 medium (Life malizing the intensity of the protein of interest against the loading Technologies, Thermo Fisher Scientific, Waltham, MA), and incubated control (normalized units). with anti-CD14–coated magnetic beads (Miltenyi Biotec, Auburn, CA). + Positive selection of CD14 cells was done, and PBM were counted. Cells
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