Canonical and non-canonical roles of complement in atherosclerosis

Area of Science:

• Cardiovascular immunology
• Complement system biology
• Atherosclerosis pathogenesis

Background:

• Cardiovascular diseases are a leading global cause of death, with atherosclerosis as a primary driver.
• The immune system, particularly the complement system, is increasingly recognized for its role in atherosclerosis.
• Both detrimental and protective functions of the complement system in atherosclerosis are being uncovered.

Purpose of the Study:

• To review the classical and emerging roles of the complement system in atherosclerosis.
• To discuss how complement activation location and function type influence disease progression.
• To explore therapeutic strategies targeting the complement system for atherosclerotic cardiovascular disease.

Main Methods:

• Literature review of classical and non-classical complement functions in atherosclerosis.
• Analysis of evidence on liver-dependent and independent complement activities.
• Synthesis of temporal and spatial aspects of complement activation in pathogenesis.

Main Results:

• Chronic activation of canonical complement drives inflammation and immune cell activation in atherosclerosis.
• Non-canonical complement activities, often liver-independent, are significant but underappreciated contributors.
• Complement activation can exhibit both atherogenic and atheroprotective effects.

Conclusions:

• The specific role of complement in atherosclerosis depends on activation location and function (canonical vs. non-canonical).
• Emerging evidence highlights the importance of non-classical complement pathways.
• Targeting the complement system offers potential therapeutic avenues for atherosclerotic cardiovascular disease.