Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany.
Nat Med. 2012 Sep;18(9):1401-6. doi: 10.1038/nm.2862.
Complement is an ancient danger-sensing system that contributes to host defense, immune surveillance and homeostasis. C5a and its G protein–coupled receptor mediate many of the proinflammatory properties of complement. Despite the key role of C5a in allergic asthma, autoimmune arthritis, sepsis and cancer, knowledge about its regulation is limited. Here we demonstrate that IgG1 immune complexes (ICs), the inhibitory IgG receptor FcγRIIB and the C-type lectin–like receptor dectin-1 suppress C5a receptor (C5aR) functions. IgG1 ICs promote the association of FcγRIIB with dectin-1, resulting in phosphorylation of Src homology 2 domain–containing inositol phosphatase (SHIP) downstream of FcγRIIB and spleen tyrosine kinase downstream of dectin-1. This pathway blocks C5aR-mediated ERK1/2 phosphorylation, C5a effector functions in vitro and C5a-dependent inflammatory responses in vivo, including peritonitis and skin blisters in experimental epidermolysis bullosa acquisita. Notably, high galactosylation of IgG N-glycans is crucial for this inhibitory property of IgG1 ICs, as it promotes the association between FcγRIIB and dectin-1. Thus, galactosylated IgG1 and FcγRIIB exert anti-inflammatory properties beyond their impact on activating FcγRs.
补体是一种古老的危险感应系统，有助于宿主防御、免疫监视和体内平衡。C5a 及其 G 蛋白偶联受体介导补体的许多促炎特性。尽管 C5a 在过敏性哮喘、自身免疫性关节炎、败血症和癌症中起着关键作用，但对其调节的了解有限。在这里，我们证明 IgG1 免疫复合物 (ICs)、抑制性 IgG 受体 FcγRIIB 和 C 型凝集素样受体 dectin-1 抑制 C5a 受体 (C5aR) 的功能。IgG1 ICs 促进 FcγRIIB 与 dectin-1 的结合，导致 FcγRIIB 下游的 Src 同源 2 结构域包含肌醇磷酸酶 (SHIP) 和 dectin-1 下游的脾酪氨酸激酶磷酸化。该途径阻断 C5aR 介导的 ERK1/2 磷酸化、体外 C5a 效应功能和体内 C5a 依赖性炎症反应，包括实验性获得性大疱性表皮松解症中的腹膜炎和皮肤水疱。值得注意的是，IgG N-糖基化的高半乳糖化对于 IgG1 ICs 的这种抑制特性至关重要，因为它促进了 FcγRIIB 与 dectin-1 的结合。因此，半乳糖化的 IgG1 和 FcγRIIB 除了对激活 FcγRs 产生影响外，还具有抗炎特性。
