Mitochondrial C5aR1 activity in macrophages controls IL-1β production underlying sterile inflammation.
Mitochondrial C5aR1 activity in macrophages controls IL-1β production underlying sterile inflammation.
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DOI：
10.1126/sciimmunol.abf2489
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发表时间：
2021-12-24
影响因子：
24.8
通讯作者：
Kemper C
中科院分区：
文献类型：
--
作者：
Niyonzima N;Rahman J;Kunz N;West EE;Freiwald T;Desai JV;Merle NS;Gidon A;Sporsheim B;Lionakis MS;Evensen K;Lindberg B;Skagen K;Skjelland M;Singh P;Haug M;Ruseva MM;Kolev M;Bibby J;Marshall O;O'Brien B;Deeks N;Afzali B;Clark RJ;Woodruff TM;Pryor M;Yang ZH;Remaley AT;Mollnes TE;Hewitt SM;Yan B;Kazemian M;Kiss MG;Binder CJ;Halvorsen B;Espevik T;Kemper C
虽然血清循环补体破坏入侵的病原体，但细胞内活性补体（称为“补体体”）作为T细胞效应子应答的细胞代谢事件的重要协调者发挥作用。目前还不清楚细胞内补体是否对骨髓免疫细胞的活性也是非冗余的。在这里，我们表明，单核细胞和巨噬细胞组成型表达补体成分（C）5和产生自分泌C5 a通过形成细胞内C5转化酶。巨噬细胞的胆固醇晶体感应诱导线粒体膜上的C5 aR 1信号传导，其通过反向电子链通量将ATP产生转向活性氧（ROS）产生和无氧糖酵解，从而有利于IL-1β的产生，无论是在转录水平还是在pro-IL-1β的加工水平。因此，缺乏巨噬细胞特异性C5 ar 1的动脉粥样硬化倾向小鼠在高胆固醇饮食下改善了心血管疾病。相反，患者不稳定动脉粥样硬化斑块中细胞产生的炎症基因特征和IL-1β通过特异性细胞渗透性C5 aR 1拮抗剂正常化。缺乏巨噬细胞自主C5系统也保护小鼠免受叶酸介导的晶体肾病。这些数据证明了C5转化酶的意外的细胞内形成，并鉴定C5 aR 1作为线粒体功能和髓样细胞炎性输出的直接调节剂。总之，这些发现表明，复合体是无菌炎症的生物学过程的贡献者，并表明靶向该系统可能对巨噬细胞依赖性疾病（如动脉粥样硬化）有益。线粒体C5 aR 1信号传导是晶体诱导的无菌炎症期间促炎巨噬细胞活性所必需的。
While serum-circulating complement destroys invading pathogens, intracellularly active complement, termed the ‘complosome’, functions as a vital orchestrator of cell-metabolic events underlying T cell effector responses. Whether intracellular complement is also non-redundant for the activity of myeloid immune cells is currently unknown. Here, we show that monocytes and macrophages constitutively express complement component (C) 5 and generate autocrine C5a via formation of an intracellular C5 convertase. Cholesterol crystal-sensing by macrophages induced C5aR1 signaling on mitochondrial membranes, which shifted ATP production via reverse electron chain flux towards reactive oxygen species (ROS) generation and anaerobic glycolysis to favor IL-1β production, both at the transcriptional level and processing of pro-IL-1β. Consequently, atherosclerosis-prone mice lacking macrophage-specific C5ar1 had ameliorated cardiovascular disease on a high-cholesterol diet. Conversely, inflammatory gene signatures and IL-1β produced by cells in unstable atherosclerotic plaques of patients were normalized by a specific cell-permeable C5aR1 antagonist. Deficiency of the macrophage cell autonomous C5 system also protected mice from crystal nephropathy mediated by folic acid. These data demonstrate the unexpected intracellular formation of a C5 convertase and identify C5aR1 as a direct modulator of mitochondrial function and inflammatory output from myeloid cells. Together, these findings suggest that the complosome is a contributor to the biologic processes underlying sterile inflammation and indicate that targeting this system could be beneficial in macrophage-dependent diseases, such as atherosclerosis. Mitochondrial C5aR1 signaling is required for pro-inflammatory macrophage activity during crystal-induced sterile inflammation.
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影响因子：
82.9
作者：
Fernandez, Dawn M.;Rahman, Adeeb H.;Giannarelli, Chiara
通讯作者：
Giannarelli, Chiara
影响因子：
16.6
作者：
Arbore G;West EE;Rahman J;Le Friec G;Niyonzima N;Pirooznia M;Tunc I;Pavlidis P;Powell N;Li Y;Liu P;Servais A;Couzi L;Fremeaux-Bacchi V;Placais L;Ferraro A;Walsh PR;Kavanagh D;Afzali B;Lavender P;Lachmann HJ;Kemper C
通讯作者：
Kemper C
影响因子：
32.4
作者：
Hess C;Kemper C
通讯作者：
Kemper C
影响因子：
4.6
作者：
Haggadone MD;Grailer JJ;Fattahi F;Zetoune FS;Ward PA
通讯作者：
Ward PA
影响因子：
64.5
作者：
Chang CH;Curtis JD;Maggi LB Jr;Faubert B;Villarino AV;O'Sullivan D;Huang SC;van der Windt GJ;Blagih J;Qiu J;Weber JD;Pearce EJ;Jones RG;Pearce EL
通讯作者：
Pearce EL