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

Antoine Dufour, Caroline L. Bellac, Ulrich Eckhard, Nestor Solis, Theo Klein, Reinhild Kappelhoff, Nikolaus Fortelny, Parker Jobin, Jacob Rozmus, Jennifer Mark, Paul Pavlidis, Vincent Dive, Sean J. Barbour and Christopher M. Overall ()
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Antoine Dufour: University of British Columbia
Caroline L. Bellac: University of British Columbia
Ulrich Eckhard: University of British Columbia
Nestor Solis: University of British Columbia
Theo Klein: University of British Columbia
Reinhild Kappelhoff: University of British Columbia
Nikolaus Fortelny: University of British Columbia
Parker Jobin: University of British Columbia
Jacob Rozmus: University of British Columbia
Jennifer Mark: University of British Columbia
Paul Pavlidis: University of British Columbia
Vincent Dive: Commissariat a l’Energie Atomique (CEA) CE-Saclay, Labex LERMIT, Service d’Ingenierie Moleculaire des Proteines
Sean J. Barbour: University of British Columbia
Christopher M. Overall: University of British Columbia

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: 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-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.

Date: 2018
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DOI: 10.1038/s41467-018-04717-4

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