Liu Zhaiyi, Zhang Jiayang, Li Shuyao, Wang Hui, Ren Baoyin, Li Jiazhi, Bao Zhiyue, Liu Jiaxin, Guo Meina, Yang Guangrui, Chen Lihong
School of Bioengineering, Dalian University of Technology, Dalian, China.
Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China.
JHEP Rep. 2023 Jul 22;5(11):100856. doi: 10.1016/j.jhepr.2023.100856. eCollection 2023 Nov.
BACKGROUND & AIMS: Circadian rhythms play significant roles in immune responses, and many inflammatory processes in liver diseases are associated with malfunctioning molecular clocks. However, the significance of the circadian clock in autoimmune hepatitis (AIH), which is characterised by immune-mediated hepatocyte destruction and extensive inflammatory cytokine production, remains unclear.
We tested the difference in susceptibility to the immune-mediated liver injury induced by concanavalin A (ConA) at various time points throughout a day in mice and analysed the effects of global, hepatocyte, or myeloid cell deletion of the core clock gene, Bmal1 (basic helix-loop-helix ARNT-like 1), on liver injury and inflammatory responses. Multiple molecular biology techniques and mice with macrophage-specific knockdown of Junb, a Bmal1 target gene, were used to investigate the involvement of Junb in the circadian control of ConA-induced hepatitis.
The susceptibility to ConA-induced liver injury is highly dependent on the timing of ConA injection. The treatment at Zeitgeber time 0 (lights on) triggers the highest mortality as well as the severest liver injury and inflammatory responses. Further study revealed that this timing effect was driven by macrophage, but not hepatocyte, Bmal1. Mechanistically, Bmal1 controls the diurnal variation of ConA-induced hepatitis by directly regulating the circadian transcription of Junb and promoting M1 macrophage activation. Inhibition of Junb in macrophages blunts the administration time-dependent effect of ConA and attenuates liver injury. Moreover, we demonstrated that Junb promotes macrophage inflammation by regulating AKT and extracellular signal-regulated kinase (ERK) signalling pathways.
Our findings uncover a critical role of the Bmal1-Junb-AKT/ERK axis in the circadian control of ConA-induced hepatitis and provide new insights into the prevention and treatment of AIH.
This study unveils a critical role of the Bmal1-Junb-AKT/ERK axis in the circadian control of ConA-induced liver injury, providing new insights into the prevention and treatment of immune-mediated hepatitis, including autoimmune hepatitis (AIH). The findings have scientific implications as they enhance our understanding of the circadian regulation of immune responses in liver diseases. Furthermore, clinically, this research offers opportunities for optimising treatment strategies in immune-mediated hepatitis by considering the timing of therapeutic interventions.
昼夜节律在免疫反应中发挥着重要作用，许多肝脏疾病中的炎症过程都与分子时钟功能失调有关。然而，昼夜节律时钟在自身免疫性肝炎（AIH）中的意义仍不清楚，AIH的特征是免疫介导的肝细胞破坏和大量炎性细胞因子产生。
我们测试了小鼠在一天中的不同时间点对刀豆蛋白A（ConA）诱导的免疫介导性肝损伤的易感性差异，并分析了核心时钟基因Bmal1（基本螺旋-环-螺旋ARNT样蛋白1）在整体、肝细胞或髓样细胞中的缺失对肝损伤和炎症反应的影响。使用多种分子生物学技术以及巨噬细胞特异性敲低Bmal1靶基因Junb的小鼠，来研究Junb在ConA诱导的肝炎的昼夜节律控制中的作用。
对ConA诱导的肝损伤的易感性高度依赖于ConA注射的时间。在生物钟时间0（光照开启）进行治疗会引发最高的死亡率以及最严重的肝损伤和炎症反应。进一步研究表明，这种时间效应是由巨噬细胞而非肝细胞中的Bmal1驱动的。从机制上讲，Bmal1通过直接调节Junb的昼夜节律转录并促进M1巨噬细胞活化来控制ConA诱导的肝炎的昼夜变化。抑制巨噬细胞中的Junb可减弱ConA的给药时间依赖性效应并减轻肝损伤。此外，我们证明Junb通过调节AKT和细胞外信号调节激酶（ERK）信号通路促进巨噬细胞炎症。
我们的研究结果揭示了Bmal1-Junb-AKT/ERK轴在ConA诱导的肝炎的昼夜节律控制中的关键作用，并为AIH的预防和治疗提供了新的见解。
本研究揭示了Bmal1-Junb-AKT/ERK轴在ConA诱导的肝损伤的昼夜节律控制中的关键作用，为包括自身免疫性肝炎（AIH）在内的免疫介导性肝炎的预防和治疗提供了新的见解。这些发现具有科学意义，因为它们增进了我们对肝脏疾病中免疫反应的昼夜节律调节的理解。此外，在临床上，这项研究通过考虑治疗干预的时间为优化免疫介导性肝炎的治疗策略提供了机会。
