IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of macrophages isolated from inflamed tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking. We found that human and mouse macrophages undergo a switch to glycolysis in response to IgG IC stimulation, mirroring macrophage metabolic changes in inflamed tissue in vivo. This metabolic reprogramming was required to generate a number of proinflammatory mediators, including IL-1β, and was dependent on mTOR and hypoxia-inducible factor (HIF)1α. Inhibition of glycolysis, or genetic depletion of HIF1α, attenuated IgG IC-induced activation of macrophages in vitro, including primary human kidney macrophages. In vivo, glycolysis inhibition led to a reduction in kidney macrophage IL-1β and reduced neutrophil recruitment in a murine model of antibody-mediated nephritis. Together, our data reveal the molecular mechanisms underpinning FcγR-mediated metabolic reprogramming in macrophages and suggest a therapeutic strategy for autoantibody-induced inflammation, including lupus nephritis.

IgG 抗体在系统性红斑狼疮 (SLE) 等自身免疫性疾病中引起炎症和器官损伤。我们研究了在免疫复合物 (IC) 相关疾病（包括 SLE 和类风湿性关节炎）中从发炎组织中分离出的巨噬细胞的代谢特征，以及 IgG Fcγ 受体交联后的代谢特征。我们发现人类和小鼠巨噬细胞响应 IgG IC 刺激而转变为糖酵解，这反映了体内炎症组织中巨噬细胞的代谢变化。这种代谢重编程需要产生许多促炎介质，包括 IL-1β，并且依赖于 mTOR 和缺氧诱导因子 (HIF)1α。糖酵解的抑制或 HIF1α 的遗传耗竭减弱了体外 IgG IC 诱导的巨噬细胞活化，包括原代人肾巨噬细胞。体内，在抗体介导的肾炎小鼠模型中，糖酵解抑制导致肾巨噬细胞 IL-1β 减少和中性粒细胞募集减少。总之，我们的数据揭示了支持 FcγR 介导的巨噬细胞代谢重编程的分子机制，并提出了一种针对自身抗体诱导的炎症（包括狼疮性肾炎）的治疗策略。