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

Abstract : 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, 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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https://hal-cea.archives-ouvertes.fr/cea-01876684
Contributor : Bruno Savelli <>
Submitted on : Tuesday, September 18, 2018 - 4:16:10 PM
Last modification on : Wednesday, July 8, 2020 - 3:36:46 AM

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Antoine Dufour, Caroline Bellac, Ulrich Eckhard, Nestor Solis, Theo Klein, et al.. C-terminal truncation of IFN-$\gamma$ inhibits proinflammatory macrophage responses and is deficient in autoimmune disease. Nature Communications, Nature Publishing Group, 2018, 9, pp.2416. ⟨10.1038/s41467-018-04717-4⟩. ⟨cea-01876684⟩

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