C-terminal truncation of IFN-γ inhibits proinflammatory macrophage responses and is deficient in autoimmune disease
| Autor: | Jacob Rozmus, Antoine Dufour, Nestor Solis, Theo Klein, Vincent Dive, Nikolaus Fortelny, Caroline L. Bellac, Paul Pavlidis, Christopher M. Overall, Sean J. Barbour, Jennifer Mark, Ulrich Eckhard, Reinhild Kappelhoff, Parker G. Jobin |
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| Přispěvatelé: | Department of Oral Biological and Medical Sciences, University of British Columbia (UBC), Centre for Blood Research (CBR), Service d'Ingénierie Moléculaire pour la Santé (ex SIMOPRO) (SIMoS), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Signalisation et physiopathologie cardiovasculaire (UMRS1180), Institut National de la Santé et de la Recherche Médicale (INSERM) |
| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine THP-1 Cells Biopsy [SDV]Life Sciences [q-bio] General Physics and Astronomy Matrix metalloproteinase Kidney Mice 0302 clinical medicine Macrophage THP1 cell line skin and connective tissue diseases lcsh:Science Mice Knockout Multidisciplinary biology Chemistry Lupus Nephritis 3. Good health Thioglycolates Female Collagen medicine.symptom Signal Transduction Science Primary Cell Culture Inflammation Matrix Metalloproteinase Inhibitors Peritonitis Article General Biochemistry Genetics and Molecular Biology Autoimmune Diseases Cell Line Proinflammatory cytokine Interferon-gamma 03 medical and health sciences Matrix Metalloproteinase 12 Synovitis medicine Animals Humans Autoimmune disease MHC class II Arthritis Macrophages General Chemistry Macrophage Activation medicine.disease Mice Inbred C57BL Disease Models Animal RAW 264.7 Cells 030104 developmental biology Proteolysis Immunology biology.protein lcsh:Q 030217 neurology & neurosurgery |
| Zdroj: | Nature Communications, Vol 9, Iss 1, Pp 1-18 (2018) Nature Communications Nature Communications, Nature Publishing Group, 2018, 9, pp.2416. ⟨10.1038/s41467-018-04717-4⟩ Nature Communications, 2018, 9, pp.2416. ⟨10.1038/s41467-018-04717-4⟩ |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-018-04717-4 |
| Popis: | 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. IFN-γ is central in inflammatory pathogenesis, response to infection and autoimmune diseases. Here the authors show that MMP12 expression is reduced in patients with SLE and that MMP12 post-translationally truncates IFN-y, inhibiting its function and affecting pathogenesis of mouse models of peritonitis, SLE and rheumatoid arthritis. |
| Databáze: | OpenAIRE |
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