Canonical and non-canonical roles of complement in atherosclerosis

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. In this Review, Kemper and colleagues discuss the canonical and non-canonical roles of the complement system in the pathogenesis of atherosclerosis and discuss potential new therapeutic strategies targeting the complement system for the prevention and treatment of atherosclerotic cardiovascular disease. 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.