C-terminal truncation of IFN-γ inhibits proinflammatory macrophage responses and is deficient in autoimmune disease.
C-terminal truncation of IFN-γ inhibits proinflammatory macrophage responses and is deficient in autoimmune disease.
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DOI：
10.1038/s41467-018-04717-4
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发表时间：
2018-06-20
影响因子：
16.6
通讯作者：
Overall CM
中科院分区：
文献类型：
--
作者：
Dufour A;Bellac CL;Eckhard U;Solis N;Klein T;Kappelhoff R;Fortelny N;Jobin P;Rozmus J;Mark J;Pavlidis P;Dive V;Barbour SJ;Overall CM
控制巨噬细胞分化和激活在炎症的启动和解决是至关重要的，以避免进展为慢性炎症和自身免疫性疾病。在这里，我们展示了巨噬细胞相关基质金属蛋白酶12（MMP 12）驱动的巨噬细胞促炎性IFN-γ激活的负反馈机制。通过在135 Glu ↓ Leu 136处截短IFN-γ的C末端，IFN-γ受体结合位点被有效去除，从而减少促炎性巨噬细胞的JAK-STAT 1信号传导和IFN-γ活化。在急性腹膜炎中，这种特征在Mmp 12-/-小鼠中不存在，而在用MMP 12特异性抑制剂治疗的Mmp 12 +/+小鼠中重现。类似地，MMP 12的缺失增加IFN-γ依赖性促炎标志物和iNOS+/MHC II类+巨噬细胞积聚，伴有更严重的淋巴结病、关节炎性滑膜炎和狼疮性肾小球肾炎。在活动性系统性红斑狼疮患者中，与接受治疗的患者或健康个体相比，MMP 12水平较低，IFN-γ水平较高。因此，IFN-γ的巨噬细胞蛋白水解截短减弱了巨噬细胞的经典活化，作为解决炎症的前奏。IFN-γ在炎症发病机制、对感染的应答和自身免疫性疾病中是中心的。在这里，作者表明，MMP 12的表达在SLE患者中减少，并且MMP 12在治疗后截短IFN-γ，抑制其功能并影响腹膜炎、SLE和类风湿性关节炎小鼠模型的发病机制。
Controlled macrophage differentiation and activation in the initiation and resolution of inflammation is crucial for averting progression to chronic inflammatory and autoimmune diseases. Here we show a negative feedback mechanism for proinflammatory IFN-γ activation of macrophages driven by macrophage-associated matrix metalloproteinase 12 (MMP12). Through C-terminal truncation of IFN-γ at 135Glu↓Leu136 the IFN-γ receptor-binding site was efficiently removed thereby reducing JAK-STAT1 signaling and IFN-γ activation of proinflammatory macrophages. In acute peritonitis this signature was absent in Mmp12–/– mice and recapitulated in Mmp12+/+ mice treated with a MMP12-specific inhibitor. Similarly, loss-of-MMP12 increases IFN-γ–dependent proinflammatory markers and iNOS+/MHC class II+ macrophage accumulation with worse lymphadenopathy, arthritic synovitis and lupus glomerulonephritis. In active human systemic lupus erythematosus, MMP12 levels were lower and IFN-γ higher compared to treated patients or healthy individuals. Hence, macrophage proteolytic truncation of IFN-γ attenuates classical activation of macrophages as a prelude for resolving inflammation. IFN-γ is central in inflammatory pathogenesis, response to infection and autoimmune diseases. Here the authors show that MMP12 expression is reduced in patients with SLE and that MMP12 post-translationally truncates IFN-y, inhibiting its function and affecting pathogenesis of mouse models of peritonitis, SLE and rheumatoid arthritis.
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DOI：
10.1161/atvbaha.110.219147
发表时间：
2011-03
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Johnson JL;Devel L;Czarny B;George SJ;Jackson CL;Rogakos V;Beau F;Yiotakis A;Newby AC;Dive V
通讯作者：
Dive V
影响因子：
14.9
作者：
Kolesnikov N;Hastings E;Keays M;Melnichuk O;Tang YA;Williams E;Dylag M;Kurbatova N;Brandizi M;Burdett T;Megy K;Pilicheva E;Rustici G;Tikhonov A;Parkinson H;Petryszak R;Sarkans U;Brazma A
通讯作者：
Brazma A
影响因子：
64.8
作者：
Houghton, A. McGarry;Hartzell, William O.;Robbins, Clinton S.;Xavier Gomis-Rueth, F.;Shapiro, Steven D.
通讯作者：
Shapiro, Steven D.
影响因子：
14.9
作者：
Barrett T;Troup DB;Wilhite SE;Ledoux P;Evangelista C;Kim IF;Tomashevsky M;Marshall KA;Phillippy KH;Sherman PM;Muertter RN;Holko M;Ayanbule O;Yefanov A;Soboleva A
通讯作者：
Soboleva A
影响因子：
4.4
作者：
Berahovich, RD;Miao, ZH;Schall, TJ
通讯作者：
Schall, TJ