@article{86070c7a598d4e6cb48754e8288d98b9,
title = "The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis",
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.",
keywords = "Bmal1, IL-7, Pd-l1, Pkm2, Stat1, checkpoint, circadian clock, macrophages, metabolism, sepsis",
author = "Wenjun Deng and Shan Zhu and Ling Zeng and Jiao Liu and Rui Kang and Minghua Yang and Lizhi Cao and Haichao Wang and Billiar, {Timothy R.} and Jianxin Jiang and Min Xie and Daolin Tang",
note = "Funding Information: We thank Christine Heiner (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by grants from the NIH ( R01GM115366 , R01CA160417 , R01AT005076 , R01GM063075 , R01GM44100 , and R01CA211070 ), the Natural Science Foundation of Guangdong Province ( 2016A030308011 ), the American Cancer Society (Research Scholar Grant RSG-16-014-01-CDD ), the National Natural Science Foundation of China ( 31671435 , 81400132 , 81772508 , and 81570154 ), the Natural Science Foundation of Hunan Province ( 2016JJ3171 ), Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme ( 2017 ), Lin He{\textquoteright}s Academician Workstation of New Medicine and Clinical Translation ( 2017 ), and International Scientific and Technology Cooperation Program of China ( 2015DFA31490 ). Funding Information: We thank Christine Heiner (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by grants from the NIH (R01GM115366, R01CA160417, R01AT005076, R01GM063075, R01GM44100, and R01CA211070), the Natural Science Foundation of Guangdong Province (2016A030308011), the American Cancer Society (Research Scholar Grant RSG-16-014-01-CDD), the National Natural Science Foundation of China (31671435, 81400132, 81772508, and 81570154), the Natural Science Foundation of Hunan Province (2016JJ3171), Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2017), Lin He's Academician Workstation of New Medicine and Clinical Translation (2017), and International Scientific and Technology Cooperation Program of China (2015DFA31490). Publisher Copyright: {\textcopyright} 2018 The Author(s)",
year = "2018",
month = jul,
day = "10",
doi = "10.1016/j.celrep.2018.06.026",
language = "English (US)",
volume = "24",
pages = "366--378",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "2",
}