Cholesterol crystals induce complement-dependent inflammasome activation and cytokine release.

Area of Science:

• Immunology
• Cardiovascular Research
• Complement System Biology

Background:

• Inflammation is integral to atherosclerosis development.
• Cholesterol crystals (CC) are early features of atherosclerotic lesions and trigger inflammation via NLRP3 inflammasome activation.

Purpose of the Study:

• To investigate if CC utilize the complement system to activate the inflammasome/caspase-1 pathway.
• To determine if complement activation modulates CC-induced cytokine production.

Main Methods:

• Assessed CC activation of classical and alternative complement pathways.
• Measured cytokine release (IL-1β, TNF) in whole blood and C5-deficient blood.
• Analyzed the role of C5a and TNF in IL-1β transcript levels.
• Investigated CC-induced complement receptor 3 (CD11b/CD18) upregulation, reactive oxygen species, and active caspase-1 production.

Main Results:

• CC activated both classical and alternative complement pathways, with C1q being crucial.
• C5a mediated CC-induced release of IL-1β and TNF; minimal cytokine production occurred in C5-deficient blood.
• C5a and TNF synergistically primed CC-induced IL-1β release by upregulating IL-1β transcripts.
• CC triggered complement-dependent upregulation of CD11b/CD18, leading to CC phagocytosis, reactive oxygen species, and active caspase-1.

Conclusions:

• Cholesterol crystals activate the complement system to induce cytokines and activate the inflammasome/caspase-1 pathway in human monocytes.
• Complement activation influences CC phagocytosis and inflammatory responses.
• Complement inhibition presents a potential therapeutic avenue for atherosclerosis.