Understanding the Mincle-FcγR crosstalk in the regulation of autoantibody-dependent inflammation

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Inflammation plays a crucial role in fighting infections, but its magnitude and duration must be tightly controlled to prevent tissue damage. Immunoglobulin G (IgG) antibodies have both pro-inflammatory and anti-inflammatory effects. Their interaction with cellular Fcgamma-receptors (FcgammaRs) and activation of the complement pathway play a critical role in immune cell activation. Recent studies have shown that IgG can also suppress inflammation through interactions with C-type lectin receptors. The macrophage inducible C-type lectin (Mincle) receptor is induced on macrophages upon activation via microbial infections or tissue damage. Mincle is involved in immunity to mycobacteria, it is upregulated in patients with rheumatoid arthritis, and Mincle signaling has been connected to cancer progression. Similar to activating Fcgamma-receptors, Mincle signals through binding to the common signaling adaptor molecule, the FcRgamma-chain. Binding of Mincle and activating FcgammaRs to FcRgamma-chain is mediated by their transmembrane domains, and competition of Mincle and FcgammaRs for FcRgamma could regulate immune cell activation. Importantly, the interaction between Mincle, FcgammaRs and the FcRgamma-chain depends on receptor localization within the plasma membrane. Our research aims to investigate the molecular crosstalk between Mincle, activating FcgammaRs, and the FcRgamma-chain within the heterogenic environment of the plasma membrane of immune cells. We will explore the competitive binding of activating FcgammaRs and of the C-type lectin receptor Mincle to the common FcRgamma-chain, characterize the receptor-specific lipid environment and their impact on receptor dimerization, receptor clustering and signaling, and the modulation of autoantibody-driven inflammation. By understanding these mechanisms, we aim to enhance our understanding of the complex mechanisms underlying Mincle-dependent modulation of autoantibody-driven inflammation on different immune cell subtypes.