Abstract

Abstract Monocytes and macrophages express Fc-gamma Receptors (FcγR) that engage IgG immune complexes such as antibody-opsonized pathogens or cancer cells to destroy them by various mechanisms including phagocytosis. FcγR-mediated phagocytosis is regulated by the concerted actions of activating FcγR and inhibitory receptors such as FcγRIIb and SIRPα. Here, we report that another ITIM-containing receptor, Platelet Endothelial Adhesion Molecule-1 (PECAM1/CD31), regulates FcγR function, and is itself regulated by FcγR activation. First, qRT-PCR and flow cytometry analyses revealed that monocyte FcγR activation leads to significant downregulation of CD31 expression, both at the message level and at surface expression. Interestingly, the kinetics of downregulation between the two varied, with surface expression reducing earlier than the message. Experiments to analyze the mechanism behind this discrepancy revealed that loss of surface expression was due to internalization, which depended predominantly on the PI3 Kinase pathway. Finally, functional analyses showed that downregulation of CD31 expression in monocytes by siRNA enhanced FcγR-mediated phagocytic ability. Together, these results suggest that CD31 functions as a checkpoint receptor that could be targeted to enhance FcγR functions in antibody-mediated therapies.

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