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: Shogo Sato, Takuya Sakurai, Junetsu Ogasawara, Motoko Takahashi, Tetsuya Izawa, Kazuhiko Imaizumi, Naoyuki Taniguchi, Hideki Ohno, Takako Kizaki
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 192 Issue 1 Pg. 407-17 (Jan 01 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 24307731 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Chemokine CCL2
• GSK4112
• Integrin beta1
• Lipopolysaccharides
• Nuclear Receptor Subfamily 1, Group D, Member 1
• Nuclear Receptor Subfamily 1, Group F, Member 1
• Thiophenes
• Vascular Cell Adhesion Molecule-1
• p38 Mitogen-Activated Protein Kinases
• Glycine

Topics

• Age Factors
• Animals
• Cell Adhesion (genetics)
• Cell Line
• Cell Movement (genetics, immunology)
• Chemokine CCL2 (genetics)
• Circadian Clocks (genetics)
• Gene Expression
• Gene Expression Regulation (drug effects)
• Glycine (analogs & derivatives, pharmacology)
• Inflammation (genetics, immunology)
• Integrin beta1 (metabolism)
• Lipopolysaccharides (immunology)
• Macrophages (immunology, metabolism)
• Macrophages, Peritoneal (immunology, metabolism)
• Male
• Mice
• Mice, Knockout
• Nuclear Receptor Subfamily 1, Group D, Member 1 (agonists, genetics)
• Nuclear Receptor Subfamily 1, Group F, Member 1 (metabolism)
• Obesity (genetics, 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)