Division of Genetics, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058 Erlangen, Germany.
Computational Biology, Department of Biology, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91058 Erlangen, Germany.
Immunity. 2023 May 9;56(5):1046-1063.e7. doi: 10.1016/j.immuni.2023.02.019. Epub 2023 Mar 21.
Immunoglobulin G (IgG) antibodies are major drivers of inflammation during infectious and autoimmune diseases. In pooled serum IgG (IVIg), however, antibodies have a potent immunomodulatory and anti-inflammatory activity, but how this is mediated is unclear. We studied IgG-dependent initiation of resolution of inflammation in cytokine- and autoantibody-driven models of rheumatoid arthritis and found IVIg sialylation inhibited joint inflammation, whereas inhibition of osteoclastogenesis was sialic acid independent. Instead, IVIg-dependent inhibition of osteoclastogenesis was abrogated in mice lacking receptors Dectin-1 or FcγRIIb. Atomistic molecular dynamics simulations and super-resolution microscopy revealed that Dectin-1 promoted FcγRIIb membrane conformations that allowed productive IgG binding and enhanced interactions with mouse and human IgG subclasses. IVIg reprogrammed monocytes via FcγRIIb-dependent signaling that required Dectin-1. Our data identify a pathogen-independent function of Dectin-1 as a co-inhibitory checkpoint for IgG-dependent inhibition of mouse and human osteoclastogenesis. These findings may have implications for therapeutic targeting of autoantibody and cytokine-driven inflammation.
免疫球蛋白 G（IgG）抗体是感染和自身免疫性疾病期间炎症的主要驱动因素。然而，在汇集的血清 IgG（IVIg）中，抗体具有强大的免疫调节和抗炎活性，但介导机制尚不清楚。我们研究了 IgG 依赖性炎症消退的启动，在细胞因子和自身抗体驱动的类风湿关节炎模型中，发现 IVIg 的唾液酸化抑制了关节炎症，而破骨细胞生成的抑制与唾液酸无关。相反，在缺乏 Dectin-1 或 FcγRIIb 受体的小鼠中，IVIg 依赖性破骨细胞生成抑制被消除。原子分子动力学模拟和超分辨率显微镜显示，Dectin-1 促进了 FcγRIIb 膜构象，允许有效结合 IgG 并增强与小鼠和人 IgG 亚类的相互作用。IVIg 通过依赖 FcγRIIb 的信号转导对单核细胞进行重编程，该信号转导需要 Dectin-1。我们的数据确定了 Dectin-1 的一种与病原体无关的功能，作为 IgG 依赖性抑制小鼠和人破骨细胞生成的共抑制检查点。这些发现可能对针对自身抗体和细胞因子驱动的炎症的治疗靶向具有重要意义。
