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

Physical Constraints and Forces Involved in Phagocytosis

“…Prior to their engagement, FcγR diffusion and clustering can be modulated by tyrosine kinase-mediated reorganization of the actin cytoskeleton, in response to environmental cues sensed through integrins, toll-like receptors (TLR) or cytokine receptors (41,(46)(47)(48)(49). Monte Carlo simulations and experimental evidence suggest that a decrease of receptor confinement and receptor clustering affect receptor engagement, implying that environmental cues can prime phagocyte responsiveness via the organization of the cortical actin cytoskeleton (41,(45)(46)(47). This effect is rather complex however, as receptor engagement also depends on the density of the ligand at the surface of the target, which can vary greatly in physiological conditions, and the affinity of the receptors for the ligand, which depends on the IgG isotype.…”

Criticality of plasma membrane lipids reflects activation state of macrophage cells

“…We have described a physical mechanism that can underpin this correlation between the immune response role of macrophage cells and the lipid composition of their plasma membranes, where signaling activation initiates. Much remains to be discovered within the ‘critical lipidomics’ paradigm, specifically direct experiments are becoming possible thanks to superresolution approaches Stone et al (2017); Veatch and Cicuta (2018); Brandsma et al (2018) , probing membrane protein copy numbers and states of aggregation and how these are affected by the proximity to lipid mixture critical points.…”

“…Macrophages are extremely versatile cells of the innate immune system able to activate and adapt their functionality depending on the specific milieu Martinez and Gordon (2014) . Following phagocytosis of material resulting from trauma, or pathogens, or detection of specific functional molecules, macrophages can change their gene regulatory state and polarize into activated states, where for example they produce immune effector molecules such as cytokines for intercellular communication Taylor et al (2005); Mosser and Edwards (2008); Brandsma et al (2018) . The responses manifested as a consequence of different stimulations have been classified in two broad activation states, based on both genetic expression profiling and phenotypic behavior: M1, or classically activated, macrophages have an enhanced bactericidal and tumoricidal capacity and produce high levels of pro-inflammatory cytokines, while M2 macrophages produce low levels of cytokines and have a wound-healing capacity by contributing to the production of collagen and extracellular matrix Martinez and Gordon (2014); Lawrence and Natoli (2011); Mosser and Edwards (2008) .…”

ADE and hyperinflammation in SARS-CoV2 infection- comparison with dengue hemorrhagic fever and feline infectious peritonitis

“…FcγRI (CD64) binds monomeric IgG with high affinity and plays an important role in priming adaptive immune responses [34] , [35] , [36] . Increased surface expression of FcγRI by inflammatory cytokines induces aggregation and potentiates the binding of immune complexes [37] . FcγRII (CD32) and FcγRIII (CD16) are low affinity receptors for IgG but are activated by immune complexes.…”