title: PER1 prevents excessive innate immune response during endotoxin-induced liver injury through regulation of macrophage recruitment in mice.
abstract: The severity of acute liver failure (ALF) induced by bacterial lipopolysaccharide (LPS) is associated with the hepatic innate immune response. The core circadian molecular clock modulates the innate immune response by controlling rhythmic pathogen recognition by the innate immune system and daily variations in cytokine gene expression. However, the molecular link between circadian genes and the innate immune system has remained unclear. Here, we showed that mice lacking the clock gene Per1 (Period1) are more susceptible to LPS/d-galactosamine (LPS/GalN)-induced macrophage-dependent ALF compared with wild-type (WT) mice. Per1 deletion caused a remarkable increase in the number of Kupffer cells (KCs) in the liver, resulting in an elevation of the levels of pro-inflammatory cytokines after LPS treatment. Loss of Per1 had no effect on the proliferation or apoptosis of macrophages; however, it enhanced the recruitment of macrophages, which was associated with an increase in CC chemokine receptor 2 (Ccr2) expression levels in monocytes/macrophages. Deletion of Ccr2 rescued d-GalN/LPS-induced liver injury in Per1(-/-) mice. We demonstrated that the upregulation of Ccr2 expression by Per1 deletion could be reversed by the synthetic peroxisome proliferator-activated receptor gamma (PPAR-γ) antagonist GW9662. Further analysis indicated that PER1 binds to PPAR-γ on the Ccr2 promoter and enhanced the inhibitory effect of PPAR-γ on Ccr2 expression. These results reveal that Per1 reduces hepatic macrophage recruitment through interaction with PPAR-γ and prevents an excessive innate immune response in endotoxin-induced liver injury.
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, China.|Cambridge Suda Genome Resource Center, Soochow University, Suzhou, China.
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.affiliation: Department of Radiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, China.
authors.forename: P
authors.initials: P
authors.lastname: Yang
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, China.
authors.forename: L
authors.initials: L
authors.lastname: Xia
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, China.
authors.forename: M
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, China.
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.affiliation: Beijing An Zhen Hospital, Capital Medical University, Beijing, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Du
authors.affiliation: Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005688:Galactosamine / Q000633:toxicity; D007113:Immunity, Innate; D007728:Kupffer Cells / Q000166:cytology; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D017114:Liver Failure, Acute / Q000209:etiology* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D056950:Period Circadian Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D018925:Chemokines; D016207:Cytokines; D008070:Lipopolysaccharides; D047495:PPAR gamma; C539023:Per1 protein, mouse; D056950:Period Circadian Proteins; D054390:Receptors, CCR2; D005688:Galactosamine