Mitochondrial C5aR1 activity in macrophages controls IL-1β production underlying sterile inflammation
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Mitochondrial C5aR1 activity in macrophages controls IL-1β production underlying sterile inflammation. / Niyonzima, Nathalie; Rahman, Jubayer; Kunz, Natalia; West, Erin E.; Freiwald, Tilo; Desai, Jigar V.; Merle, Nicolas S.; Gidon, Alexandre; Sporsheim, Bjørnar; Lionakis, Michail S.; Evensen, Kristin; Lindberg, Beate; Skagen, Karolina; Skjelland, Mona; Singh, Parul; Haug, Markus; Ruseva, Marieta M.; Kolev, Martin; Bibby, Jack; Marshall, Olivia; O’Brien, Brett; Deeks, Nigel; Afzali, Behdad; Clark, Richard J.; Woodruff, Trent M.; Pryor, Milton; Yang, Zhi-Hong; Remaley, Alan T.; Mollnes, Tom E.; Hewitt, Stephen M.; Yan, Bingyu; Kazemian, Majid; Kiss, Máté G.; Binder, Christoph J.; Halvorsen, Bente; Espevik, Terje; Kemper, Claudia.
in: SCI IMMUNOL, Jahrgang 6, Nr. 66, eabf2489, 24.12.2021, S. eabf2489.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Mitochondrial C5aR1 activity in macrophages controls IL-1β production underlying sterile inflammation
AU - Niyonzima, Nathalie
AU - Rahman, Jubayer
AU - Kunz, Natalia
AU - West, Erin E.
AU - Freiwald, Tilo
AU - Desai, Jigar V.
AU - Merle, Nicolas S.
AU - Gidon, Alexandre
AU - Sporsheim, Bjørnar
AU - Lionakis, Michail S.
AU - Evensen, Kristin
AU - Lindberg, Beate
AU - Skagen, Karolina
AU - Skjelland, Mona
AU - Singh, Parul
AU - Haug, Markus
AU - Ruseva, Marieta M.
AU - Kolev, Martin
AU - Bibby, Jack
AU - Marshall, Olivia
AU - O’Brien, Brett
AU - Deeks, Nigel
AU - Afzali, Behdad
AU - Clark, Richard J.
AU - Woodruff, Trent M.
AU - Pryor, Milton
AU - Yang, Zhi-Hong
AU - Remaley, Alan T.
AU - Mollnes, Tom E.
AU - Hewitt, Stephen M.
AU - Yan, Bingyu
AU - Kazemian, Majid
AU - Kiss, Máté G.
AU - Binder, Christoph J.
AU - Halvorsen, Bente
AU - Espevik, Terje
AU - Kemper, Claudia
PY - 2021/12/24
Y1 - 2021/12/24
N2 - While serum-circulating complement destroys invading pathogens, intracellularly active complement, termed the “complosome,” functions as a vital orchestrator of cell-metabolic events underlying T cell effector responses. Whether intracellular complement is also nonredundant for the activity of myeloid immune cells is currently unknown. Here, we show that monocytes and macrophages constitutively express complement component (C) 5 and generate autocrine C5a via formation of an intracellular C5 convertase. Cholesterol crystal sensing by macrophages induced C5aR1 signaling on mitochondrial membranes, which shifted ATP production via reverse electron chain flux toward reactive oxygen species generation and anaerobic glycolysis to favor IL-1β production, both at the transcriptional level and processing of pro–IL-1β. Consequently, atherosclerosis-prone mice lacking macrophage-specific C5ar1 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.
AB - While serum-circulating complement destroys invading pathogens, intracellularly active complement, termed the “complosome,” functions as a vital orchestrator of cell-metabolic events underlying T cell effector responses. Whether intracellular complement is also nonredundant for the activity of myeloid immune cells is currently unknown. Here, we show that monocytes and macrophages constitutively express complement component (C) 5 and generate autocrine C5a via formation of an intracellular C5 convertase. Cholesterol crystal sensing by macrophages induced C5aR1 signaling on mitochondrial membranes, which shifted ATP production via reverse electron chain flux toward reactive oxygen species generation and anaerobic glycolysis to favor IL-1β production, both at the transcriptional level and processing of pro–IL-1β. Consequently, atherosclerosis-prone mice lacking macrophage-specific C5ar1 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.
UR - https://doi.org/10.1126/sciimmunol.abf2489
U2 - 10.1126/sciimmunol.abf2489
DO - 10.1126/sciimmunol.abf2489
M3 - SCORING: Journal article
C2 - 34932384
VL - 6
SP - eabf2489
JO - SCI IMMUNOL
JF - SCI IMMUNOL
SN - 2470-9468
IS - 66
M1 - eabf2489
ER -