CD31 Acts as a Checkpoint Molecule and Is Modulated by Fc?R-Mediated Signaling in Monocytes.

ABSTRACT: Monocytes and macrophages express Fc?R that engage IgG immune complexes such as Ab-opsonized pathogens or cancer cells to destroy them by various mechanisms, including phagocytosis. Fc?R-mediated phagocytosis is regulated by the concerted actions of activating Fc?R and inhibitory receptors, such as Fc?RIIb and SIRP?. In this study, we report that another ITIM-containing receptor, PECAM1/CD31, regulates Fc?R function and is itself regulated by Fc?R activation. First, quantitative RT-PCR and flow cytometry analyses revealed that human monocyte Fc?R activation leads to a significant downregulation of CD31 expression, both at the message level and at surface expression, mainly mediated through Fc?RIIa. 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 Fc?R internalization. Finally, functional analyses showed that the downregulation of CD31 expression in monocytes by small interfering RNA enhanced Fc?R-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 Fc?R functions in Ab-mediated therapies.

SUBMITTER: Merchand-Reyes G 

PROVIDER: S-EPMC6904527 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature