A Circadian Clock Gene, Rev-erbα, Modulates the Inflammatory Function of Macrophages through the Negative Regulation of Ccl2 Expression

Dec 6, 2013Journal of immunology (Baltimore, Md. : 1950)

The body’s daily clock gene Rev-erbα may reduce inflammation by lowering Ccl2 in immune cells

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Abstract

Rev-erbα regulates the inflammatory function of macrophages by directly modulating Ccl2 expression.

Disruption of circadian rhythms is linked to various clinical conditions, including cancer and metabolic syndrome.
Chronic inflammation, characterized by the infiltration of inflammatory macrophages, may trigger type 2 diabetes and cardiovascular disease.
In conditions like aging or obesity, Rev-erbα gene expression is reduced in macrophages from C57BL/6J mice.
Activation of Rev-erbα through agonists or overexpression in macrophages suppresses Ccl2 production in response to LPS endotoxin.
Rev-erbα directly binds to the Ccl2 promoter region to repress its expression and also inhibits CCL2-activated signaling pathways.
Macrophages lacking Rev-erbα exhibit increased Ccl2 expression, suggesting a role for Rev-erbα in regulating macrophage inflammation.

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

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A Circadian Clock Gene, Rev-erbα, Modulates the Inflammatory Function of Macrophages through the Negative Regulation of Ccl2 Expression

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