| First Author | Dufour A | Year | 2018 |
| Journal | Nat Commun | Volume | 9 |
| Issue | 1 | Pages | 2416 |
| PubMed ID | 29925830 | Mgi Jnum | J:271279 |
| Mgi Id | MGI:6209336 | Doi | 10.1038/s41467-018-04717-4 |
| Citation | Dufour A, et al. (2018) C-terminal truncation of IFN-gamma inhibits proinflammatory macrophage responses and is deficient in autoimmune disease. Nat Commun 9(1):2416 |
| abstractText | 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. |
