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

    研究成果: Article

    94 引用 (Scopus)

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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.

    元の言語English
    ページ(範囲)407-417
    ページ数11
    ジャーナルJournal of Immunology
    192
    発行部数1
    DOI
    出版物ステータスPublished - 2014 1 1

      フィンガープリント

    ASJC Scopus subject areas

    • Immunology

    これを引用

    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