Repository logo
 

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

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Kiss, Máté G 
Papac-Miličević, Nikolina 
Porsch, Florentina 
Tsiantoulas, Dimitrios 
Hendrikx, Tim 

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.

Description

Keywords

atherosclerosis, cell-autonomous complement, complement factor H, complement protein C3, efferocytosis, inflammation, local complement production, macrophages, plaque necrosis, Animals, Humans, Mice, Atherosclerosis, Complement C3, Complement Factor H, Inflammation, Macrophages

Journal Title

Immunity

Conference Name

Journal ISSN

1074-7613
1097-4180

Volume Title

Publisher

Elsevier BV
Sponsorship
British Heart Foundation (SP/F/20/150010)
British Heart Foundation (CH/10/001/27642)