TY - JOUR
T1 - Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates atherosclerosis
AU - Kiss, Máté G
AU - Papac-Miličević, Nikolina
AU - Porsch, Florentina
AU - Tsiantoulas, Dimitrios
AU - Hendrikx, Tim
AU - Takaoka, Minoru
AU - Dinh, Huy Q
AU - Narzt, Marie-Sophie
AU - Göderle, Laura
AU - Ozsvár-Kozma, Mária
AU - Schuster, Michael
AU - Fortelny, Nikolaus
AU - Hladik, Anastasiya
AU - Knapp, Sylvia
AU - Gruber, Florian
AU - Pickering, Matthew C
AU - Bock, Christoph
AU - Swirski, Filip K
AU - Ley, Klaus
AU - Zernecke, Alma
AU - Cochain, Clément
AU - Kemper, Claudia
AU - Mallat, Ziad
AU - Binder, Christoph J
N1 - Copyright © 2023 Elsevier Inc. All rights reserved.
PY - 2023/8/8
Y1 - 2023/8/8
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Mice
KW - Atherosclerosis/metabolism
KW - Complement C3/genetics
KW - Complement Factor H/genetics
KW - Inflammation
KW - Macrophages/metabolism
KW - atherosclerosis
KW - efferocytosis
KW - cell-autonomous complement
KW - macrophages
KW - local complement production
KW - inflammation
KW - plaque necrosis
KW - complement protein C3
KW - complement factor H
UR - http://www.scopus.com/inward/record.url?scp=85166594911&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/37499656/
UR - https://www.sciencedirect.com/science/article/pii/S1074761323002832
U2 - 10.1016/j.immuni.2023.06.026
DO - 10.1016/j.immuni.2023.06.026
M3 - Article
C2 - 37499656
SN - 1074-7613
VL - 56
SP - 1809-1824.e10
JO - IMMUNITY
JF - IMMUNITY
IS - 8
ER -