| First Author | Sato S | Year | 2014 |
| Journal | J Immunol | Volume | 192 |
| Issue | 1 | Pages | 407-17 |
| PubMed ID | 24307731 | Mgi Jnum | J:207168 |
| Mgi Id | MGI:5554621 | Doi | 10.4049/jimmunol.1301982 |
| Citation | Sato S, et al. (2014) A circadian clock gene, Rev-erbalpha, modulates the inflammatory function of macrophages through the negative regulation of Ccl2 expression. J Immunol 192(1):407-17 |
| abstractText | Disruption of the circadian rhythm is a contributory factor to clinical and pathophysiological conditions, including cancer, the metabolic syndrome, and inflammation. Chronic and systemic inflammation are a potential trigger of type 2 diabetes and cardiovascular disease and are caused by the infiltration of large numbers of inflammatory macrophages into tissue. Although recent studies identified the circadian clock gene Rev-erbalpha, a member of the orphan nuclear receptors, as a key mediator between clockwork and inflammation, the molecular mechanism remains unknown. In this study, we demonstrate that Rev-erbalpha modulates the inflammatory function of macrophages through the direct regulation of Ccl2 expression. Clinical conditions associated with chronic and systemic inflammation, such as aging or obesity, dampened Rev-erbalpha gene expression in peritoneal macrophages from C57BL/6J mice. Rev-erbalpha agonists or overexpression of Rev-erbalpha in the murine macrophage cell line RAW264 suppressed the induction of Ccl2 following an LPS endotoxin challenge. We discovered that Rev-erbalpha represses Ccl2 expression directly through a Rev-erbalpha-binding motif in the Ccl2 promoter region. Rev-erbalpha also suppressed CCL2-activated signals, ERK and p38, which was recovered by the addition of exogenous CCL2. Further, Rev-erbalpha impaired cell adhesion and migration, which are inflammatory responses activated through the ERK- and p38-signaling pathways, respectively. Peritoneal macrophages from mice lacking Rev-erbalpha display increases in Ccl2 expression. These data suggest that Rev-erbalpha regulates the inflammatory infiltration of macrophages through the suppression of Ccl2 expression. Therefore, Rev-erbalpha may be a key link between aging- or obesity-associated impairment of clockwork and inflammation. |
