Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates atherosclerosis.
Máté G Kiss, Nikolina Papac-Miličević, Florentina Porsch, Dimitrios Tsiantoulas, Tim Hendrikx, Minoru Takaoka, Huy Q Dinh, Marie-Sophie Narzt, Laura Göderle, Mária Ozsvár-Kozma, Michael Schuster, Nikolaus Fortelny, Anastasiya Hladik, Sylvia Knapp, Florian Gruber, Matthew C Pickering, Christoph Bock, Filip K Swirski, Klaus Ley, Alma Zernecke, Clément Cochain, Claudia Kemper, Ziad Mallat, Christoph J Binder
Immunity 2023 Aug 08Complement factor H (CFH) negatively regulates consumption of complement component 3 (C3), thereby restricting complement activation. Genetic variants in CFH predispose to chronic inflammatory disease. Here, we examined the impact of CFH on atherosclerosis development. In a mouse model of atherosclerosis, CFH deficiency limited plaque necrosis in a C3-dependent manner. Deletion of CFH in monocyte-derived inflammatory macrophages propagated uncontrolled cell-autonomous C3 consumption without downstream C5 activation and heightened efferocytotic capacity. Among leukocytes, Cfh expression was restricted to monocytes and macrophages, increased during inflammation, and coincided with the accumulation of intracellular C3. Macrophage-derived CFH was sufficient to dampen resolution of inflammation, and hematopoietic deletion of CFH in atherosclerosis-prone mice promoted lesional efferocytosis and reduced plaque size. Furthermore, we identified monocyte-derived inflammatory macrophages expressing C3 and CFH in human atherosclerotic plaques. Our findings reveal a regulatory axis wherein CFH controls intracellular C3 levels of macrophages in a cell-autonomous manner, evidencing the importance of on-site complement regulation in the pathogenesis of inflammatory diseases. Copyright © 2023 Elsevier Inc. All rights reserved.
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Máté G Kiss, Nikolina Papac-Miličević, Florentina Porsch, Dimitrios Tsiantoulas, Tim Hendrikx, Minoru Takaoka, Huy Q Dinh, Marie-Sophie Narzt, Laura Göderle, Mária Ozsvár-Kozma, Michael Schuster, Nikolaus Fortelny, Anastasiya Hladik, Sylvia Knapp, Florian Gruber, Matthew C Pickering, Christoph Bock, Filip K Swirski, Klaus Ley, Alma Zernecke, Clément Cochain, Claudia Kemper, Ziad Mallat, Christoph J Binder. Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates atherosclerosis. Immunity. 2023 Aug 08;56(8):1809-1824.e10
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PMID: 37499656
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