Wang T, Wang Z, Yang P, Xia L, Zhou M, Wang S, Du Jie, Zhang J
Center for Molecular Metabolism, Nanjing University of Science and Technology, Nanjing, China.
Cambridge Suda Genome Resource Center, Soochow University, Suzhou, China.
Cell Death Dis. 2016 Apr 7;7(4):e2176. doi: 10.1038/cddis.2016.9.
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.
细菌脂多糖（LPS）诱导的急性肝衰竭（ALF）的严重程度与肝脏固有免疫反应相关。核心昼夜节律分子时钟通过控制固有免疫系统对病原体的节律性识别以及细胞因子基因表达的每日变化来调节固有免疫反应。然而，昼夜节律基因与固有免疫系统之间的分子联系仍不清楚。在此，我们表明，与野生型（WT）小鼠相比，缺乏时钟基因Per1（周期蛋白1）的小鼠更容易受到LPS/d-半乳糖胺（LPS/GalN）诱导的巨噬细胞依赖性ALF的影响。Per1缺失导致肝脏中库普弗细胞（KC）数量显著增加，从而导致LPS处理后促炎细胞因子水平升高。Per1缺失对巨噬细胞的增殖或凋亡没有影响；然而，它增强了巨噬细胞的募集，这与单核细胞/巨噬细胞中CC趋化因子受体2（Ccr2）表达水平的增加有关。删除Ccr2可挽救Per1（-/-）小鼠中d-GalN/LPS诱导的肝损伤。我们证明，Per1缺失引起的Ccr2表达上调可被合成的过氧化物酶体增殖物激活受体γ（PPAR-γ）拮抗剂GW9662逆转。进一步分析表明，PER1与Ccr2启动子上的PPAR-γ结合，并增强了PPAR-γ对Ccr2表达的抑制作用。这些结果表明，Per1通过与PPAR-γ相互作用减少肝脏巨噬细胞募集，并防止内毒素诱导的肝损伤中过度的固有免疫反应。
