Mechanisms of inside-out signaling of the high-affinity IgG receptor Fc?RI.

ABSTRACT: Fc receptors (FcRs) are an important bridge between the innate and adaptive immune system. Fc gamma receptor I (Fc?RI; 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-? ( TNF?) and interferon-? ( IFN?), increases the binding of Fc?RI 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 Fc?RI 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 Fc?RI inside-out signaling, although the phosphorylation of Fc?RI itself was unaffected. Furthermore, the antibody-dependent cytotoxic activity of human neutrophils toward CD20-expressing tumor cells was increased after stimulation with TNF? and IFN?. These results suggest that nanoscale reorganization of Fc?RI, stimulated by cytokine-induced, inside-out signaling, enhances Fc?RI cellular effector functions.

SUBMITTER: Brandsma AM 

PROVIDER: S-EPMC7521114 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature