Protective Role of C3aR (C3a Anaphylatoxin Receptor) Against Atherosclerosis in Atherosclerosis-Prone Mice

Abstract

Objective: Emerging evidence suggests that C3aR (C3a anaphylatoxin receptor) signaling has protective roles in various inflammatory-related diseases. However, its role in atherosclerosis has been unknown. The purpose of the study was to investigate the possible protective role of C3aR in aortic atherosclerosis and explore molecular and cellular mechanisms involved in the protection. Approach and Results: C3ar −/− /Apoe −/− mice were generated by cross-breeding of atherosclerosis-prone Apoe −/− mice and C3ar −/− mice. C3ar −/− /Apoe −/− mice and Apoe −/− mice (as a control) underwent high-fat diet for 16 weeks were assessed for (1) atherosclerotic plaque burden, (2) aortic tissue inflammation, (3) recruitment of CD11b + leukocytes into atherosclerotic lesions, and (4) systemic inflammatory responses. Compared with Apoe −/− mice, C3ar −/− /Apoe −/− mice developed more severe atherosclerosis. In addition, C3ar −/− /Apoe −/− mice have increased local production of proinflammatory mediators (eg, CCL2 [chemokine (C-C motif) ligand 2], TNF [tumor necrosis factor]-α) and infiltration of monocyte/macrophage in aortic tissue, and their lesional macrophages displayed an M1-like phenotype. Local pathological changes were associated with enhanced systemic inflammatory responses (ie, elevated plasma levels of CCL2 and TNF-α, increased circulating inflammatory cells). In vitro analyses using peritoneal macrophages showed that C3a stimulation resulted in upregulation of M2-associated signaling and molecules, but suppression of M1-associated signaling and molecules, supporting the roles of C3a/C3aR axis in mediating anti-inflammatory response and promoting M2 macrophage polarization. Conclusions: Our findings demonstrate a protective role for C3aR in the development of atherosclerosis and suggest that C3aR confers the protection through C3a/C3aR axis–mediated negative regulation of proinflammatory responses and modulation of macrophage toward the anti-inflammatory phenotype.

Activation of the C3a anaphylatoxin receptor inhibits keratinocyte proliferation by regulating keratin 6, keratin 16, and keratin 17 in psoriasis

“…C3aR also served a protective role against the development of atherosclerosis in atherosclerosis‐prone mice, involving suppressed proinflammatory responses and macrophage skewing toward an M2‐like phenotype. These findings are consistent with other findings showing that the C3a–C3aR axis protected against renal injury in inflammation‐associated disorders 26 …”

“…These findings are consistent with other findings showing that the C3a-C3aR axis protected against renal injury in inflammationassociated disorders. 26 Psoriasis is a chronic inflammatory skin disease, and complement proteins may help link innate autoinflammatory and adaptive autoimmune responses to its pathogenesis. Several reports have indicated that keratinocytes are a rich source of complement components, including C3, complement factor H, and complement factor I.…”

Regulatory T Cell-Related Gene Biomarkers in the Deterioration of Atherosclerosis

“…C3AR1 is an orphan G protein-coupled receptor for C3a, a potent pro-inflammatory and chemotactic peptide during complement activation. A recent study showed that in apolipoprotein-E-deficient mice, silencing C3AR1 might result in a more serious atherosclerotic burden and inflammatory response (45) Although the roles of most hub DETregRGs have not been established in atherosclerosis, we found their expression patterns between advanced and early carotid plaques were consistent across independent datasets. Indeed, these genes have also been implicated in the development of other immuneinflammatory diseases such as asthma and rheumatoid arthritis (48,49).…”

“…C3AR1 is an orphan G protein-coupled receptor for C3a, a potent pro-inflammatory and chemotactic peptide during complement activation. A recent study showed that in apolipoprotein-E-deficient mice, silencing C3AR1 might result in a more serious atherosclerotic burden and inflammatory response ( 45 ). As a binding receptor of C-C motif chemokine ligand 5, CCR1 is expressed in various cell types such as macrophages, T lymphocytes, and Th1 cells.…”

C3 Deficiency Leads to Increased Angiogenesis and Elevated Pro-Angiogenic Leukocyte Recruitment in Ischemic Muscle Tissue

“…However, C3 seems to act anti-inflammatory as well. For example, the C3a receptor has been shown to play a protective role in atherosclerosis [ 31 ].…”