Circadian control of ConA-induced acute liver injury and inflammatory response via Bmal1 regulation of Junb

Zhaiyi Liu; Jiayang Zhang; Shuyao Li; Hui Wang; Baoyin Ren; Jiazhi Li; Zhiyue Bao; Jiaxin Liu; Meina Guo; Guangrui Yang; Lihong Chen

doi:10.1016/j.jhepr.2023.100856

Circadian control of ConA-induced acute liver injury and inflammatory response via Bmal1 regulation of Junb

JHEP Rep. 2023 Jul 22;5(11):100856. doi: 10.1016/j.jhepr.2023.100856. eCollection 2023 Nov.

Authors

Zhaiyi Liu^{1

2}, Jiayang Zhang³, Shuyao Li², Hui Wang², Baoyin Ren¹, Jiazhi Li², Zhiyue Bao¹, Jiaxin Liu², Meina Guo², Guangrui Yang⁴, Lihong Chen²

Affiliations

¹ School of Bioengineering, Dalian University of Technology, Dalian, China.
² Advanced Institute for Medical Sciences, Dalian Medical University, Dalian, China.
³ Wuhu Hospital and Health Science Center, East China Normal University, Shanghai, China.
⁴ School of Clinical Medicine, Shanghai University of Medicine and Health Sciences, Shanghai, China.

Abstract

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.

Methods: 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.

Results: 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.

Conclusions: 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.

Impact and implications: 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.

Keywords: Autoimmune hepatitis; Bmal1; Circadian rhythm; Junb; Macrophage.