C-terminal truncation of IFN-γ 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-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.

journal_name

Nat Commun

journal_title

Nature communications

authors

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

doi

10.1038/s41467-018-04717-4

subject

Has Abstract

pub_date

2018-06-20 00:00:00

pages

2416

issue

1

issn

2041-1723

pii

10.1038/s41467-018-04717-4

journal_volume

9

pub_type

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