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

doi:10.1016/j.immuni.2023.06.026

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 ZerneckeClément Cochain, Claudia Kemper, Ziad Mallat, Christoph J. Binder^*

^*Korrespondierende/r Autor/-in für diese Arbeit

Institut für Systemische Entzündungsforschung

58 Zitate (Scopus)

Abstract

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.

Originalsprache	Englisch
Zeitschrift	Immunity
Jahrgang	56
Ausgabenummer	8
Seiten (von - bis)	1809-1824.e10
ISSN	1074-7613
DOIs	https://doi.org/10.1016/j.immuni.2023.06.026
Publikationsstatus	Veröffentlicht - 08.08.2023

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We thank Thomas Winkler-Penz and the Biomedical Sequencing Facility as well as the Anna Spiegel Animal Facility, especially Astrid Fabry for excellent technical support. We are grateful to Christina Schüller and Robert Kralovics for providing us with CD45.1 mice. We thank Arif Yurdagul Jr. and Ira Tabas for providing us with the in situ efferocytosis assay protocol. This work was supported by the doctoral program Cell Communication in Health and Disease (CCHD) ( DK W1205-B09 , to M.G.K. and F.P.), by SFB Lipotox F30 ( F 3015-B19 ), both funded by the Austrian Science Fund (FWF), by the Leducq Foundation ( TNE-20CVD03 ) to C.J.B., and by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; project number 324392634-TR221 to A.Z., 458539578 and 471705758 to C.C., and 453989101-SFB1525 and 432915089 to A.Z. and C.C.).

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SDG 3 – Gesundheit und Wohlergehen

Strategische Forschungsbereiche und Zentren

Forschungsschwerpunkt: Infektion und Entzündung - Zentrum für Infektions- und Entzündungsforschung Lübeck (ZIEL)

DFG-Fachsystematik

2.21-05 Immunologie

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10.1016/j.immuni.2023.06.026

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Kiss, M. G., Papac-Miličević, N., Porsch, F., Tsiantoulas, D., Hendrikx, T., Takaoka, M., Dinh, H. Q., Narzt, M. S., Göderle, L., Ozsvár-Kozma, M., Schuster, M., Fortelny, N., Hladik, A., Knapp, S., Gruber, F., Pickering, M. C., Bock, C., Swirski, F. K., Ley, K., ... Binder, C. J. (2023). Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates atherosclerosis. Immunity, 56(8), 1809-1824.e10. https://doi.org/10.1016/j.immuni.2023.06.026

@article{2fbf18a9b2c74d03b78e424ffdcd1f8d,

title = "Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates atherosclerosis",

abstract = "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.",

author = "Kiss, \{M{\'a}t{\'e} G.\} and Nikolina Papac-Mili{\v c}evi{\'c} and Florentina Porsch and Dimitrios Tsiantoulas and Tim Hendrikx and Minoru Takaoka and Dinh, \{Huy Q.\} and Narzt, \{Marie Sophie\} and Laura G{\"o}derle and M{\'a}ria Ozsv{\'a}r-Kozma and Michael Schuster and Nikolaus Fortelny and Anastasiya Hladik and Sylvia Knapp and Florian Gruber and Pickering, \{Matthew C.\} and Christoph Bock and Swirski, \{Filip K.\} and Klaus Ley and Alma Zernecke and Cl{\'e}ment Cochain and Claudia Kemper and Ziad Mallat and Binder, \{Christoph J.\}",

note = "Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",

year = "2023",

month = aug,

day = "8",

doi = "10.1016/j.immuni.2023.06.026",

language = "English",

volume = "56",

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journal = "Immunity",

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Kiss, MG, Papac-Miličević, N, Porsch, F, Tsiantoulas, D, Hendrikx, T, Takaoka, M, Dinh, HQ, Narzt, MS, Göderle, L, Ozsvár-Kozma, M, Schuster, M, Fortelny, N, Hladik, A, Knapp, S, Gruber, F, Pickering, MC, Bock, C, Swirski, FK, Ley, K, Zernecke, A, Cochain, C, Kemper, C, Mallat, Z & Binder, CJ 2023, 'Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates atherosclerosis', Immunity, Jg. 56, Nr. 8, S. 1809-1824.e10. https://doi.org/10.1016/j.immuni.2023.06.026

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.

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 - https://www.scopus.com/pages/publications/85166594911

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 -

Cell-autonomous regulation of complement C3 by factor H limits macrophage efferocytosis and exacerbates atherosclerosis

Abstract

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