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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

107 Scopus citations

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.

Original languageEnglish
Pages (from-to)366-378
Number of pages13
JournalCell Reports
Volume24
Issue number2
DOIs
StatePublished - 10 Jul 2018
Externally publishedYes

Keywords

  • Bmal1
  • IL-7
  • Pd-l1
  • Pkm2
  • Stat1
  • checkpoint
  • circadian clock
  • macrophages
  • metabolism
  • sepsis

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