A circadian clock gene, Rev-erbα, modulates the inflammatory function of macrophages through the negative regulation of Ccl2 expression

Shogo Sato, Takuya Sakurai, Junetsu Ogasawara, Motoko Takahashi, Tetsuya Izawa, Kazuhiko Imaizumi, Naoyuki Taniguchi, Hideki Ohno, Takako Kizaki

    Research output: Contribution to journalArticle

    105 Citations (Scopus)

    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-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.

    Original languageEnglish
    Pages (from-to)407-417
    Number of pages11
    JournalJournal of Immunology
    Volume192
    Issue number1
    DOIs
    Publication statusPublished - 2014 Jan 1

    ASJC Scopus subject areas

    • Immunology

    Fingerprint Dive into the research topics of 'A circadian clock gene, Rev-erbα, modulates the inflammatory function of macrophages through the negative regulation of Ccl2 expression'. Together they form a unique fingerprint.

  • Cite this

    Sato, S., Sakurai, T., Ogasawara, J., Takahashi, M., Izawa, T., Imaizumi, K., Taniguchi, N., Ohno, H., & Kizaki, T. (2014). A circadian clock gene, Rev-erbα, modulates the inflammatory function of macrophages through the negative regulation of Ccl2 expression. Journal of Immunology, 192(1), 407-417. https://doi.org/10.4049/jimmunol.1301982