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.
Highlights
Recent studies in mice demonstrated that the actions of macrophages in Acute liver failure (ALF) largely depend on the recruitment of monocytes and macrophages into the liver.[4,5] Chemokines may be critically involved in this process of leukocyte recruitment and activation
One of the most potent chemokines identified for monocytes and macrophages is monocyte chemoattractant protein 1 (MCP-1), which acts by binding to the CC chemokine receptor 2 (CCR2)
Given the intimate association between the innate immune response and circadian rhythms, we explored the role of the clock gene Per[1] (Period1) in ALF induced by administration of D-galactosamine (GalN)/LPS, which is a well-established model similar to ALF in the clinical setting
Summary
Recent studies in mice demonstrated that the actions of macrophages in ALF largely depend on the recruitment of monocytes and macrophages into the liver.[4,5] Chemokines may be critically involved in this process of leukocyte recruitment and activation. One of the most potent chemokines identified for monocytes and macrophages is MCP-1, which acts by binding to the CC chemokine receptor 2 (CCR2). Evidence from both murine and human studies suggests that CCR2/. The circadian clock controls Toll-like receptor 9-mediated innate and adaptive immunity.[13] Blood leukocyte numbers have long been known to exhibit circadian oscillations.[14,15] Recent. We further demonstrated that deletion of Per[1] alleviates the inhibitory effect of peroxisome proliferator-activated receptor gamma (PPAR-γ) on Ccr[2] expression, resulting in an increase in the number of KCs in Per1− / − mice
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