Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates atherosclerosis
Copyright © 2023 Elsevier Inc. All rights reserved..
Complement 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:56 |
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| Enthalten in: |
Immunity - 56(2023), 8 vom: 08. Aug., Seite 1809-1824.e10 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Kiss, Máté G [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 11.08.2023 Date Revised 13.03.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.immuni.2023.06.026 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 245 | 1 | 0 | |a Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates atherosclerosis |
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| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2023 Elsevier Inc. All rights reserved. | ||
| 520 | |a Complement 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a atherosclerosis | |
| 650 | 4 | |a cell-autonomous complement | |
| 650 | 4 | |a complement factor H | |
| 650 | 4 | |a complement protein C3 | |
| 650 | 4 | |a efferocytosis | |
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| 650 | 4 | |a plaque necrosis | |
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| 700 | 1 | |a Papac-Miličević, Nikolina |e verfasserin |4 aut | |
| 700 | 1 | |a Porsch, Florentina |e verfasserin |4 aut | |
| 700 | 1 | |a Tsiantoulas, Dimitrios |e verfasserin |4 aut | |
| 700 | 1 | |a Hendrikx, Tim |e verfasserin |4 aut | |
| 700 | 1 | |a Takaoka, Minoru |e verfasserin |4 aut | |
| 700 | 1 | |a Dinh, Huy Q |e verfasserin |4 aut | |
| 700 | 1 | |a Narzt, Marie-Sophie |e verfasserin |4 aut | |
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| 700 | 1 | |a Ozsvár-Kozma, Mária |e verfasserin |4 aut | |
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| 700 | 1 | |a Binder, Christoph J |e verfasserin |4 aut | |
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