C-terminal truncation of IFN-gamma inhibits proinflammatory macrophage responses and is deficient in autoimmune disease #MMPMID29925830
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
Nat Commun 2018[Jun]; 9 (1): 2416 PMID29925830show ga
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 downward arrowLeu136 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, loss-of-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.
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Nat+Commun 2018 ; 9 (1): 2416
