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

炎症在抗击感染方面起着至关重要的作用，但其规模和持续时间必须严格控制，以防止组织损伤。免疫球蛋白G抗体既有促炎作用，又有抗炎作用。它们与细胞内FcGamma受体的相互作用和补体途径的激活在免疫细胞激活中起着关键作用。最近的研究表明，免疫球蛋白还可以通过与C型凝集素受体的相互作用来抑制炎症。巨噬细胞可诱导的C型凝集素受体(Mincle)是通过微生物感染或组织损伤激活巨噬细胞后诱导的。Mincle参与了对分枝杆菌的免疫，它在类风湿性关节炎患者中上调，Mincle信号与癌症进展有关。与激活Fcr-受体类似，Mincle通过与共同的信号适配器分子FcR-Gamma链结合来传递信号。Mincle和FcGammaRs与FcRGamma链的结合和激活是由它们的跨膜结构域介导的，Mincle和FcGammaRs对FcRGamma的竞争可以调节免疫细胞的激活。重要的是，Mincle、FcGammaRs和FcRGamma链之间的相互作用依赖于受体在质膜中的定位。我们的研究旨在研究免疫细胞质膜异源环境中激活FcGammaRs的Mincle与FcRGamma链之间的分子串扰。我们将探索激活的FcGammaRs和C型凝集素受体Mincle与共同的FcRGamma链的竞争结合，表征受体特有的脂环境及其对受体二聚化、受体聚集和信号传递的影响，以及自身抗体驱动的炎症的调节。通过了解这些机制，我们的目的是加强我们对Mincle依赖的自身抗体驱动的炎症对不同免疫细胞亚型的调节的复杂机制的理解。

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.