title: A circadian clock gene, Rev-erbα, modulates the inflammatory function of macrophages through the negative regulation of Ccl2 expression.
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.
authors.affiliation: Department of Molecular Predictive Medicine and Sport Science, School of Medicine, Kyorin University, Mitaka, Tokyo 181-8611, Japan;
authors.forename: Shogo
authors.initials: S
authors.lastname: Sato
authors.forename: Takuya
authors.initials: T
authors.lastname: Sakurai
authors.forename: Junetsu
authors.initials: J
authors.lastname: Ogasawara
authors.forename: Motoko
authors.initials: M
authors.lastname: Takahashi
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Izawa
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Imaizumi
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Taniguchi
authors.forename: Hideki
authors.initials: H
authors.lastname: Ohno
authors.forename: Takako
authors.initials: T
authors.lastname: Kizaki
mesh_terms: D000367:Age Factors; D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D018932:Chemokine CCL2 / Q000235:genetics*; D057906:Circadian Clocks / Q000235:genetics*; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics* / Q000276:immunology*; D019012:Integrin beta1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000819:agonists / Q000235:genetics*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000276:immunology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020218:Response Elements; D013876:Thiophenes / Q000494:pharmacology; D015533:Transcriptional Activation; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D018932:Chemokine CCL2; C572356:GSK4112; D019012:Integrin beta1; D008070:Lipopolysaccharides; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D013876:Thiophenes; D019010:Vascular Cell Adhesion Molecule-1; D048051:p38 Mitogen-Activated Protein Kinases; D005998:Glycine