Mitochondrial C5aR1 activity in macrophages controls IL-1β production underlying sterile inflammation

著者: Nathalie Niyonzima, Jubayer Rahman, Natalia Kunz, Erin E. West, Tilo Freiwald, Jigar V. Desai, Nicolas S. Merle, Alexandre Gidon, Bjørnar Sporsheim, Michail S. Lionakis, Kristin Evensen, Beate Rikken Lindberg, Karolina Skagen, Mona Skjelland, Parul Singh, Markus Haug, Marieta M. Ruseva, Martin Kolev, Jack Bibby, Olivia Marshall, Brett A. O’Brien, Nigel Deeks, Behdad Afzali, Richard J. Clark, Trent M. Woodruff, Milton Pryor, Zhihong Yang, Alan T. Remaley, Tom Eirik Mollnes, Stephen M. Hewitt, Bingyu Yan, Majid Kazemian, Máté G. Kiss, Christoph J. Binder, Bente Halvorsen, Terje Espevik, Claudia Kemper - Science Immunology 2021 被引用: 161

had ameliorated cardiovascular disease on a high-cholesterol diet. Conversely, inflammatory gene signatures and IL-1β produced by cells in unstable atherosclerotic plaques of patients were normalized by a specific cell-permeable C5aR1 antagonist. Deficiency of the macrophage cell-autonomous C5 system also protected mice from crystal nephropathy mediated by folic acid. These data demonstrate the unexpected intracellular formation of a C5 convertase and identify C5aR1 as a direct modulator of mitochondrial function and inflammatory output from myeloid cells. Together, these findings suggest that the complosome is a contributor to the biologic processes underlying sterile inflammation and indicate that targeting this system could be beneficial in macrophage-dependent diseases, such as atherosclerosis.