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.

中文翻译：

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IFN-γ的C端截短可抑制促炎性巨噬细胞应答，并缺乏自身免疫性疾病。

炎症的起始和消退中受控的巨噬细胞分化和活化对于避免进展为慢性炎症和自身免疫疾病至关重要。在这里，我们显示了由巨噬细胞相关基质金属蛋白酶12（MMP12）驱动的巨噬细胞促炎性IFN-γ激活的负反馈机制。通过在135Glu↓Leu136处进行IFN-γ的C端截短，可以有效地去除IFN-γ受体结合位点，从而减少JAK-STAT1信号转导和促炎巨噬细胞的IFN-γ活化。在急性腹膜炎中，该标记在Mmp12 ^-/-小鼠中不存在，而在用MMP12特异性抑制剂治疗的Mmp12 ^{+ / +}小鼠中概括。同样，MMP12缺失会增加IFN-γ依赖性促炎标志物和iNOS ⁺/ MHC II类⁺巨噬细胞蓄积，伴有更严重的淋巴结病，关节炎滑膜炎和狼疮性肾小球肾炎。与治疗的患者或健康个体相比，活跃的人系统性红斑狼疮的MMP12水平较低，而IFN-γ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。