The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis
Wenjun Deng,
Shan Zhu,
Ling Zeng,
Jiao Liu,
Rui Kang,
Minghua Yang,
Lizhi Cao,
Haichao Wang,
Timothy R. Billiar,
Jianxin Jiang,
Min Xie,
Daolin Tang
Affiliations
Wenjun Deng
The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China; Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
Shan Zhu
The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China
Ling Zeng
State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research Institute for Traffic Medicine of People’s Liberation Army, Daping Hospital, Third Military Medical University, Chongqing 400042, China
Jiao Liu
The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China
Rui Kang
Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
Minghua Yang
Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
Lizhi Cao
Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
Haichao Wang
Laboratory of Emergency Medicine, North Shore University Hospital and The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA
Timothy R. Billiar
Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
Jianxin Jiang
State Key Laboratory of Trauma, Burns and Combined Injury, Research Institute of Surgery, Research Institute for Traffic Medicine of People’s Liberation Army, Daping Hospital, Third Military Medical University, Chongqing 400042, China
Min Xie
Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China; Corresponding author
Daolin Tang
The Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Protein Modification and Degradation of Guangdong Higher Education Institutes, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, Guangdong 510510, China; Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; Corresponding author
Summary: Sepsis and septic shock are associated with life-threatening organ dysfunction caused by an impaired host response to infections. Although circadian clock disturbance impairs the early inflammatory response, its impact on post-septic immunosuppression remains poorly elucidated. Here, we show that Bmal1, a core circadian clock gene, plays a role in the regulation of host immune responses in experimental sepsis. Mechanistically, Bmal1 deficiency in macrophages increases PKM2 expression and lactate production, which is required for expression of the immune checkpoint protein PD-L1 in a STAT1-dependent manner. Consequently, targeted ablation of Pkm2 in myeloid cells or administration of anti-PD-L1-neutralizing antibody or supplementation with recombinant interleukin-7 (IL-7) facilitates microbial clearance, inhibits T cell apoptosis, reduces multiple organ dysfunction, and reduces septic death in Bmal1-deficient mice. Collectively, these findings suggest that the circadian clock controls the immune checkpoint pathway in macrophages and therefore represents a potential therapeutic target for lethal infection. : Deng et al. demonstrate that BMAL1 plays a role in preventing the development of a sepsis phenotype during severe infection through counter-regulating PD-L1 expression and T cell exhaustion. These findings indicate that targeting the circadian clock and immunometabolism pathway has potential for treating infectious diseases that lead to lethal sepsis. Keywords: Bmal1, Pkm2, Pd-l1, Stat1, IL-7, sepsis, checkpoint, circadian clock, metabolism, macrophages
