Canonical and non-canonical roles of complement in atherosclerosis

Pasquale Maffia; Claudio Mauro; Ayden Case; Claudia Kemper

doi:10.1038/s41569-024-01016-y

Canonical and non-canonical roles of complement in atherosclerosis

Pasquale Maffia, Claudio Mauro, Ayden Case, Claudia Kemper^*

^*Corresponding author for this work

Inflammation and Ageing

Research output: Contribution to journal › Review article › peer-review

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Abstract

Cardiovascular diseases are the leading cause of death globally, and atherosclerosis is the major contributor to the development and progression of cardiovascular diseases. Immune responses have a central role in the pathogenesis of atherosclerosis, with the complement system being an acknowledged contributor. Chronic activation of liver-derived and serum-circulating canonical complement sustains endothelial inflammation and innate immune cell activation, and deposition of complement activation fragments on inflamed endothelial cells is a hallmark of atherosclerotic plaques. However, increasing evidence indicates that liver-independent, cell-autonomous and non-canonical complement activities are underappreciated contributors to atherosclerosis. Furthermore, complement activation can also have atheroprotective properties. These specific detrimental or beneficial contributions of the complement system to the pathogenesis of atherosclerosis are dictated by the location of complement activation and engagement of its canonical versus non-canonical functions in a temporal fashion during atherosclerosis progression. In this Review, we summarize the classical and the emerging non-classical roles of the complement system in the pathogenesis of atherosclerosis and discuss potential strategies for therapeutic modulation of complement for the prevention and treatment of atherosclerotic cardiovascular disease.

Original language	English
Journal	Nature Reviews Cardiology
Early online date	10 Apr 2024
DOIs	https://doi.org/10.1038/s41569-024-01016-y
Publication status	E-pub ahead of print - 10 Apr 2024

Bibliographical note

Acknowledgements:
Work in the Kemper laboratory is supported in part by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute (ZIA/hl006223 to C.K.), the NIH-OXCAM Scholars Program and a Gates Cambridge Scholarship (A.C.). Work in the Maffia laboratory is supported in part by British Heart Foundation grants (PG/19/84/34771, FS/19/56/34893 A, PG/21/10541, PG/21/10557, PG/21/10634) and the Italian Ministry of University and Research (MUR) PRIN 2022 (2022T45AXH). C.M. is supported by a British Heart Foundation Senior Research Fellowship (FS/SBSRF/22/31031).

© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

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10.1038/s41569-024-01016-y

MaffiaP2024Canonical
This version of the article has been accepted for publication, after peer review (when applicable) and is subject to Springer Nature’s AM terms of use, but is not the Version of Record and does not reflect post-acceptance improvements, or any corrections. The Version of Record is available online at: http://dx.doi.org/10.1038/s41569-024-01016-y
Accepted author manuscript, 1.61 MBLicence: Other (please specify with Rights Statement)

Investigating and exploiting lactate signalling in athero-immunometabolism
Mauro, C. (Principal Investigator)
British Heart Foundation
1/02/23 → 31/01/28
Project: Research

Cite this

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title = "Canonical and non-canonical roles of complement in atherosclerosis",

abstract = "Cardiovascular diseases are the leading cause of death globally, and atherosclerosis is the major contributor to the development and progression of cardiovascular diseases. Immune responses have a central role in the pathogenesis of atherosclerosis, with the complement system being an acknowledged contributor. Chronic activation of liver-derived and serum-circulating canonical complement sustains endothelial inflammation and innate immune cell activation, and deposition of complement activation fragments on inflamed endothelial cells is a hallmark of atherosclerotic plaques. However, increasing evidence indicates that liver-independent, cell-autonomous and non-canonical complement activities are underappreciated contributors to atherosclerosis. Furthermore, complement activation can also have atheroprotective properties. These specific detrimental or beneficial contributions of the complement system to the pathogenesis of atherosclerosis are dictated by the location of complement activation and engagement of its canonical versus non-canonical functions in a temporal fashion during atherosclerosis progression. In this Review, we summarize the classical and the emerging non-classical roles of the complement system in the pathogenesis of atherosclerosis and discuss potential strategies for therapeutic modulation of complement for the prevention and treatment of atherosclerotic cardiovascular disease.",

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note = "Acknowledgements: Work in the Kemper laboratory is supported in part by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute (ZIA/hl006223 to C.K.), the NIH-OXCAM Scholars Program and a Gates Cambridge Scholarship (A.C.). Work in the Maffia laboratory is supported in part by British Heart Foundation grants (PG/19/84/34771, FS/19/56/34893 A, PG/21/10541, PG/21/10557, PG/21/10634) and the Italian Ministry of University and Research (MUR) PRIN 2022 (2022T45AXH). C.M. is supported by a British Heart Foundation Senior Research Fellowship (FS/SBSRF/22/31031). {\textcopyright} 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",

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N2 - Cardiovascular diseases are the leading cause of death globally, and atherosclerosis is the major contributor to the development and progression of cardiovascular diseases. Immune responses have a central role in the pathogenesis of atherosclerosis, with the complement system being an acknowledged contributor. Chronic activation of liver-derived and serum-circulating canonical complement sustains endothelial inflammation and innate immune cell activation, and deposition of complement activation fragments on inflamed endothelial cells is a hallmark of atherosclerotic plaques. However, increasing evidence indicates that liver-independent, cell-autonomous and non-canonical complement activities are underappreciated contributors to atherosclerosis. Furthermore, complement activation can also have atheroprotective properties. These specific detrimental or beneficial contributions of the complement system to the pathogenesis of atherosclerosis are dictated by the location of complement activation and engagement of its canonical versus non-canonical functions in a temporal fashion during atherosclerosis progression. In this Review, we summarize the classical and the emerging non-classical roles of the complement system in the pathogenesis of atherosclerosis and discuss potential strategies for therapeutic modulation of complement for the prevention and treatment of atherosclerotic cardiovascular disease.

AB - Cardiovascular diseases are the leading cause of death globally, and atherosclerosis is the major contributor to the development and progression of cardiovascular diseases. Immune responses have a central role in the pathogenesis of atherosclerosis, with the complement system being an acknowledged contributor. Chronic activation of liver-derived and serum-circulating canonical complement sustains endothelial inflammation and innate immune cell activation, and deposition of complement activation fragments on inflamed endothelial cells is a hallmark of atherosclerotic plaques. However, increasing evidence indicates that liver-independent, cell-autonomous and non-canonical complement activities are underappreciated contributors to atherosclerosis. Furthermore, complement activation can also have atheroprotective properties. These specific detrimental or beneficial contributions of the complement system to the pathogenesis of atherosclerosis are dictated by the location of complement activation and engagement of its canonical versus non-canonical functions in a temporal fashion during atherosclerosis progression. In this Review, we summarize the classical and the emerging non-classical roles of the complement system in the pathogenesis of atherosclerosis and discuss potential strategies for therapeutic modulation of complement for the prevention and treatment of atherosclerotic cardiovascular disease.

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ER -

Canonical and non-canonical roles of complement in atherosclerosis

Abstract

Bibliographical note

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Investigating and exploiting lactate signalling in athero-immunometabolism

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