Research ArticleFC RECEPTORS

Mechanisms of inside-out signaling of the high-affinity IgG receptor FcγRI

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Sci. Signal.  24 Jul 2018:
Vol. 11, Issue 540, eaaq0891
DOI: 10.1126/scisignal.aaq0891

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Inside-out Fc receptor activation

Important for the activation of integrin adhesion molecules, “inside-out” activation is triggered by cytoplasmic signals that increase the affinity of the integrin for its ligand. Using super-resolution microscopy, Brandsma et al. found that cytokine stimulation similarly augments Fc receptor avidity by increasing the size of FcγRI clusters on the surface of monocytes. Pharmacological inhibitors of actin rearrangement and the phosphatase PP1 reduced receptor clustering. Cytokine-driven FcγRI clustering also correlated with the increased FcγR-dependent cytolytic activity of human neutrophils. Together, these findings suggest that FcR clustering stimulated by cytokines drives the inside-out activation of FcγRI.

Abstract

Fc receptors (FcRs) are an important bridge between the innate and adaptive immune system. Fc gamma receptor I (FcγRI; CD64), the high-affinity receptor for immunoglobulin G (IgG), plays roles in inflammation, autoimmune responses, and immunotherapy. Stimulation of myeloid cells with cytokines, such as tumor necrosis factor–α ( TNFα) and interferon-γ ( IFNγ), increases the binding of FcγRI to immune complexes (ICs), such as antibody-opsonized pathogens or tumor cells, through a process known as “inside-out” signaling. Using super-resolution imaging, we found that stimulation of cells with IL-3 also enhanced the clustering of FcγRI both before and after exposure to ICs. This increased clustering was dependent on an intact actin cytoskeleton. We found that chemical inhibition of the activity of the phosphatase PP1 reduced FcγRI inside-out signaling, although the phosphorylation of FcγRI itself was unaffected. Furthermore, the antibody-dependent cytotoxic activity of human neutrophils toward CD20-expressing tumor cells was increased after stimulation with TNFα and IFNγ. These results suggest that nanoscale reorganization of FcγRI, stimulated by cytokine-induced, inside-out signaling, enhances FcγRI cellular effector functions.

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