A circadian clock gene, Rev-erb, modulates the inflammatory function of macrophages through the negative regulation of Ccl2 expression.
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abstract
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-erb, 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-erb 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-erb gene expression in peritoneal macrophages from C57BL/6J mice. Rev-erb agonists or overexpression of Rev-erb in the murine macrophage cell line RAW264 suppressed the induction of Ccl2 following an LPS endotoxin challenge. We discovered that Rev-erb represses Ccl2 expression directly through a Rev-erb-binding motif in the Ccl2 promoter region. Rev-erb also suppressed CCL2-activated signals, ERK and p38, which was recovered by the addition of exogenous CCL2. Further, Rev-erb impaired cell adhesion and migration, which are inflammatory responses activated through the ERK- and p38-signaling pathways, respectively. Peritoneal macrophages from mice lacking Rev-erb display increases in Ccl2 expression. These data suggest that Rev-erb regulates the inflammatory infiltration of macrophages through the suppression of Ccl2 expression. Therefore, Rev-erb may be a key link between aging- or obesity-associated impairment of clockwork and inflammation.
