Abstract
Inflammation is associated with development of atherosclerosis, and cholesterol crystals (CC) have long been recognized as a hallmark of atherosclerotic lesions. CC appear early in the atheroma development and trigger inflammation by NLRP3 inflammasome activation. In this study we hypothesized whether CC employ the complement system to activate inflammasome/caspase-1, leading to release of mature IL-1β, and whether complement activation regulates CC-induced cytokine production. In this study we describe that CC activated both the classical and alternative complement pathways, and C1q was found to be crucial for the activation. CC employed C5a in the release of a number of cytokines in whole blood, including IL-1β and TNF. CC induced minimal amounts of cytokines in C5-deficient whole blood, until reconstituted with C5. Furthermore, C5a and TNF in combination acted as a potent primer for CC-induced IL-1β release by increasing IL-1β transcripts. CC-induced complement activation resulted in upregulation of complement receptor 3 (CD11b/CD18), leading to phagocytosis of CC. Also, CC mounted a complement-dependent production of reactive oxygen species and active caspase-1. We conclude that CC employ the complement system to induce cytokines and activate the inflammasome/caspase-1 by regulating several cellular responses in human monocytes. In light of this, complement inhibition might be an interesting therapeutic approach for treatment of atherosclerosis.
Highlights
We and others have shown that cholesterol crystals (CC)- induced inflammation is a critical contributor to atheroma development and progression in experimental atherosclerosis [4, 7]
Our data demonstrate that CC induced a robust complement activation that resulted in high amounts of C3bc and the soluble terminal complement complex (TCC)
We found a clear activation of the classical pathway by the CC suggesting an initial activation of the classical pathway by C1q binding to the CC surface
Summary
Cholesterol Crystals Induce Complement-Dependent Inflammasome Activation and Cytokine Release We conclude that CC employ the complement system to induce cytokines and activate the inflammasome/caspase-1 by regulating several cellular responses in human monocytes. In this study we report that CC activate both the classical and alternative complement pathways that result in cytokine release.
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