The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis

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 Bm...

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Published in:	Cell reports (Cambridge) 2018-07, Vol.24 (2), p.366-378
Main Authors:	Deng, Wenjun, Zhu, Shan, Zeng, Ling, Liu, Jiao, Kang, Rui, Yang, Minghua, Cao, Lizhi, Wang, Haichao, Billiar, Timothy R., Jiang, Jianxin, Xie, Min, Tang, Daolin
Format:	Article
Language:	eng
Subjects:	Animals ARNTL Transcription Factors - metabolism B7-H1 Antigen - metabolism Bmal1 checkpoint circadian clock Circadian Clocks Humans IL-7 Lactates - metabolism Macrophage Activation macrophages metabolism Mice, Inbred C57BL Mice, Knockout Monocytes - metabolism Myeloid Cells - metabolism Pd-l1 Phenotype Pkm2 Pyruvate Kinase - metabolism sepsis Sepsis - immunology Sepsis - physiopathology Stat1 STAT1 Transcription Factor - metabolism THP-1 Cells Up-Regulation
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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. [Display omitted] •Bmal1 deficiency in myeloid cells increases polymicrobial infection in mice•The circadian clock blocks PD-L1 expression in activated macrophages and monocytes•PKM2 is required for STAT1-dependent PD-L1 upregulation•PD-L1 pathway contributes to septic death in Bmal1Mye−/− mice 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.
ISSN:	2211-1247 2211-1247