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C-terminal truncation of IFN-? 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-? activation of macrophages driven by macrophage-associated matrix metalloproteinase 12 (MMP12). Through C-terminal truncation of IFN-? at 135Glu?Leu136 the IFN-? receptor-binding site was efficiently removed thereby reducing JAK-STAT1 signaling and IFN-? 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-?-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-? higher compared to treated patients or healthy individuals. Hence, macrophage proteolytic truncation of IFN-? attenuates classical activation of macrophages as a prelude for resolving inflammation.

SUBMITTER: Dufour A

PROVIDER: S-EPMC6010466 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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

Dufour Antoine A Bellac Caroline L CL Eckhard Ulrich U Solis Nestor N Klein Theo T Kappelhoff Reinhild R Fortelny Nikolaus N Jobin Parker P Rozmus Jacob J Mark Jennifer J Pavlidis Paul P Dive Vincent V Barbour Sean J SJ Overall Christopher M CM

Nature communications 20180620 1

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 ...[more]

PMID: 29925830

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Project description:BackgroundTumor-associated macrophages (TAMs) are an important subset of innate immune cells in the tumor microenvironment, and they are pivotal regulators of tumor-promoting inflammation and tumor progression. Evidence has proven that TAM numbers are substantially increased in cancers, and most of these TAMs are polarized toward the alternatively activated M2 phenotype; Thus, these TAMs strongly promote the progression of cancer diseases. Type 1 innate lymphocytes (ILC1s) are present in high numbers in intestinal tissues and are characterized by the expression of the transcription factor T-bet and the secretion of interferon (IFN)-γ, which can promote macrophages to polarize toward the classically activated antitumor M1 phenotype. However, the relationship between these two cell subsets in colon cancer remains unclear.MethodsFlow cytometry was used to determine the percentages of M1-like macrophages, M2-like macrophages and ILC1s in colon cancer tissues and paracancerous healthy colon tissues in the AOM/DSS-induced mouse model of colon cancer. Furthermore, ILC1s were isolated and bone marrow-derived macrophages were generated to analyze the crosstalk that occurred between these cells when cocultured in vitro. Moreover, ILC1s were adoptively transferred or inhibited in vivo to explore the effects of ILC1s on tumor-infiltrating macrophages and tumor growth.ResultsWe found that the percentages of M1-like macrophages and ILC1s were decreased in colon cancer tissues, and these populations were positively correlated. ILC1s promoted the polarization of macrophages toward the classically activated M1-like phenotype in vitro, and this effect could be blocked by an anti-IFN-γ antibody. The in vivo results showed that the administration of the Group 1 innate lymphocyte-blocking anti-NK1.1 antibody decreased the number of M1-like macrophages in the tumor tissues of MC38 tumor-bearing mice and promoted tumor growth, and adoptive transfer of ILC1s inhibited tumors and increased the percentage of M1-like macrophages in MC38 tumor-bearing mice.ConclusionsOur studies preliminarily prove for the first time that ILC1s promote the activation of M1-like macrophages by secreting IFN-γ and inhibit the progression of colon cancer, which may provide insight into immunotherapeutic approaches for colon cancer.

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

Publications

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

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