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

了解 Mincle-FcγR 串扰在自身抗体依赖性炎症调节中的作用

• 批准号: 534019561
• 负责人: Professor Dr. Rainer Böckmann
• 金额: --
• 依托单位: Professur Computational Biology
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/534019561?language=en
• 关键词: Understanding; Mincle; Fc; crosstalk; regulation

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.

炎症在对抗感染方面起着至关重要的作用，但必须严格控制其程度和持续时间，以防止组织损伤。免疫球蛋白G（IgG）抗体具有促炎和抗炎作用。它们与细胞Fc γ受体（Fc γ R）的相互作用和补体途径的活化在免疫细胞活化中起关键作用。最近的研究表明，IgG还可以通过与C型凝集素受体相互作用来抑制炎症。巨噬细胞可诱导的C型凝集素（Mincle）受体通过微生物感染或组织损伤激活后在巨噬细胞上诱导。Mincle参与对分枝杆菌的免疫，在类风湿性关节炎患者中上调，并且Mincle信号传导与癌症进展有关。与激活Fc γ受体类似，Mincle通过与共同的信号传导衔接子分子FcR γ链结合来进行信号传导。Mincle和FcgammaR与FcR γ链的结合是通过其跨膜结构域介导的，并且Mincle和FcgammaR对FcR γ的竞争可以调节免疫细胞活化。重要的是，Mincle、Fc γ R和Fc γ链之间的相互作用取决于质膜内的受体定位。我们的研究旨在研究Mincle、活化Fc γ R和免疫细胞质膜的异质性环境内的Fc γ R-链之间的分子串扰。我们将探讨竞争性结合的激活FcgammaRs和C型凝集素受体Mincle的共同FcRgamma链，表征受体特异性脂质环境及其对受体二聚化，受体聚集和信号传导的影响，以及自身抗体驱动的炎症的调制。通过了解这些机制，我们的目标是提高我们对不同免疫细胞亚型上自身抗体驱动的炎症的Mincle依赖性调节的复杂机制的理解。