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) Vol. 24; no. 2; pp. 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	Journal Article
Language	English
Published	United States Elsevier Inc 10.07.2018 Elsevier
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 checkpoint macrophages Pkm2 Stat1 metabolism Pd-l1 circadian clock Bmal1 sepsis IL-7
Online Access	Get full text
ISSN	2211-1247 2211-1247
DOI	10.1016/j.celrep.2018.06.026

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Abstract	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.
AbstractList	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. 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. 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 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. 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.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.
Author	Xie, Min Wang, Haichao Tang, Daolin Billiar, Timothy R. Deng, Wenjun Yang, Minghua Liu, Jiao Kang, Rui Jiang, Jianxin Zhu, Shan Zeng, Ling Cao, Lizhi
AuthorAffiliation	3 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 6 Lead Contact 5 Laboratory of Emergency Medicine, North Shore University Hospital and The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA 1 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 4 Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA 2 Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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Copyright	2018 The Author(s) Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
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Keywords	checkpoint macrophages Pkm2 Stat1 metabolism Pd-l1 circadian clock Bmal1 sepsis IL-7
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Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 AUTHOR CONTRIBUTIONS D.T. and M.X. conceived and designed the experiments. W.D., S.Z., L.Z., J.L., R.K., M.Y., L.C., J.J., M.X., and D.T. performed the experiments. W.D., H.W., T.R.B., J.J., M.X., and D.T. analyzed the data. D.T. wrote the paper. H.W. and T.R.B. edited the manuscript.
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SubjectTerms	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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Title	The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis
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