C-terminal truncation of IFN-γ inhibits proinflammatory macrophage responses and is deficient in autoimmune disease

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-gamma activation of macrophages driven by macrophage-associated matrix metalloproteinase 12 (MMP12). Through C-terminal truncation of IFN-gamma at 135Glu. Leu136 the IFN-gamma receptor-binding site was efficiently removed thereby reducing JAK-STAT1 signaling and IFN-gamma 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, lossof- MMP12 increases IFN-gamma-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-gamma higher compared to treated patients or healthy individuals. Hence, macrophage proteolytic truncation of IFN-gamma attenuates classical activation of macrophages as a prelude for resolving inflammation.