CD31 Acts as a Checkpoint Molecule and Is Modulated by FcγR-Mediated Signaling in Monocytes

Abstract

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 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.

Prognostic Implication of the Expression Level of PECAM-1 in Non-small Cell Lung Cancer

“…However, the role of PECAM-1 in LC remains unclear ( 45 – 50 ). Giovanna et al found that PECAM-1 acts as a checkpoint molecule and can negatively regulate FcγR-mediated phagocytosis by monocytes and macrophages, and downregulation of PECAM-1 correlated with decreased survival of chronic lymphocytic leukemia cells ( 51 , 52 ). Virman et al found that high expression of PECAM-1 was significantly associated with improved survival.…”

Camouflage strategies for therapeutic exosomes evasion from phagocytosis

“…CD31 is mainly associated with vascular biology, participating in important processes as cell-to-cell adhesion, transmigration of monocytes and inflammation [70] , [71] . This molecule is composed of 3 structures, six extracellular domains, an intramembrane domain and a cytoplasmic tail that have two immunoreceptor tyrosine-based inhibition motifs (ITIMs) that have multiple ligand, like SHP-1 and -2, SH2 domain containing inositol phosphatase 2, PI3K, and phospholipase C-ɣ1 [72] .…”

Early pregnancy human decidua gamma/delta T cells exhibit tissue resident and specific functional characteristics

“…These data demonstrated that the activity of early decidua γδ T cells was higher in the maternal-fetal interface. Moreover, high expression of CD31, an endothelial cell adhesion molecule [47], was also detected in early decidua, which may be related to γδ T cells resident in early decidua. It is an indisputable fact that cytokines in the maternal fetal interface play an important role in the establishment and maintenance of normal pregnancy.…”