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 - Publisher Copyright:
© 2023 Elsevier Inc.
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.
UR - http://www.scopus.com/inward/record.url?scp=85166594911&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2023.06.026
DO - 10.1016/j.immuni.2023.06.026
M3 - Journal articles
C2 - 37499656
AN - SCOPUS:85166594911
SN - 1074-7613
VL - 56
SP - 1809-1824.e10
JO - Immunity
JF - Immunity
IS - 8
ER -
