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Canonical and non-canonical roles of complement in atherosclerosis

Nature Reviews Cardiology (2024)Cite this article

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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.

Key points

  • Complement activities are compartmentalized, with liver-derived complement functioning systemically in the blood and lymph, (immune) cell-derived complement locally in tissue matrices, and intracellularly active complement within subcellular compartments and organelles.

  • The intracellular complement functions across immune and non-immune cells, where it controls cell proliferation, the responses to damage-associated molecular patterns and pathogen-associated molecular patterns, and the return to homeostasis, through modulation of basic cell physiological pathways.

  • Complement activities affect atherosclerosis pathogenesis on all three functional levels: systemically (endothelial cell activation), locally (immune cell effector functions) and intracellularly (control of cell metabolism and efferocytosis).

  • Complement activities can have pro-atherogenic and anti-atherogenic effects, depending on the location (systemic versus tissue) and time of action during atherosclerotic pathogenesis.

  • Targeting complement successfully for the management of atherosclerosis might require combinational modulation of systemic and locally and intracellularly active complement.

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Fig. 1: The complement system and its location-driven activities.
Fig. 2: Complement-mediated contributions to the pathogenesis of atherosclerosis.
Fig. 3: Emerging concepts on the complement system in atherosclerosis.

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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).

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Authors and Affiliations

  1. School of Infection & Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

    Pasquale Maffia

  2. Department of Pharmacy, School of Medicine and Surgery, University of Naples Federico II, Naples, Italy

    Pasquale Maffia

  3. Africa-Europe Cluster of Research Excellence (CoRE) in Non-Communicable Diseases & Multimorbidity, African Research Universities Alliance (ARUA) & The Guild, Accra, Ghana

    Pasquale Maffia

  4. Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK

    Claudio Mauro

  5. Heart and Lung Research Institute, University of Cambridge, Cambridge, UK

    Ayden Case

  6. Complement and Inflammation Research Section, National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, MD, USA

    Ayden Case & Claudia Kemper

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  1. Pasquale Maffia
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  4. Claudia Kemper
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All authors researched literature for the article, made substantial contributions to discussions of the content and wrote, reviewed or edited the manuscript before submission.

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Nature Reviews Cardiology thanks Christoph J. Binder, who co-reviewed with Mate Kiss; Harald Langer; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Maffia, P., Mauro, C., Case, A. et al. Canonical and non-canonical roles of complement in atherosclerosis. Nat Rev Cardiol (2024). https://doi.org/10.1038/s41569-024-01016-y

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