RRC ID 44781
Author Sato S, Sakurai T, Ogasawara J, Takahashi M, Izawa T, Imaizumi K, Taniguchi N, Ohno H, Kizaki T.
Title A circadian clock gene, Rev-erbα, modulates the inflammatory function of macrophages through the negative regulation of Ccl2 expression.
Journal J Immunol
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.
Volume 192(1)
Pages 407-17
Published 2014-1-1
DOI 10.4049/jimmunol.1301982
PII jimmunol.1301982
PMID 24307731
MeSH Age Factors Animals Cell Adhesion / genetics Cell Line Cell Movement / genetics Cell Movement / immunology Chemokine CCL2 / genetics* Circadian Clocks / genetics* Gene Expression Gene Expression Regulation* / drug effects Glycine / analogs & derivatives Glycine / pharmacology Inflammation / genetics* Inflammation / immunology* Integrin beta1 / metabolism Lipopolysaccharides / immunology Macrophages / immunology Macrophages / metabolism* Macrophages, Peritoneal / immunology Macrophages, Peritoneal / metabolism Male Mice Mice, Knockout Nuclear Receptor Subfamily 1, Group D, Member 1 / agonists Nuclear Receptor Subfamily 1, Group D, Member 1 / genetics* Nuclear Receptor Subfamily 1, Group F, Member 1 / metabolism Obesity / genetics Obesity / immunology Phosphorylation Promoter Regions, Genetic Protein Binding Response Elements Thiophenes / pharmacology Transcriptional Activation Vascular Cell Adhesion Molecule-1 / metabolism p38 Mitogen-Activated Protein Kinases / metabolism
IF 4.886
Times Cited 100
Human and Animal Cells RAW 264(RCB0535)