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The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis.
- Source :
-
Cell reports [Cell Rep] 2018 Jul 10; Vol. 24 (2), pp. 366-378. - Publication Year :
- 2018
-
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.<br /> (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Subjects :
- ARNTL Transcription Factors metabolism
Animals
B7-H1 Antigen metabolism
Humans
Lactates metabolism
Macrophage Activation
Mice, Inbred C57BL
Mice, Knockout
Monocytes metabolism
Myeloid Cells metabolism
Phenotype
Pyruvate Kinase metabolism
STAT1 Transcription Factor metabolism
THP-1 Cells
Up-Regulation
Circadian Clocks
Sepsis immunology
Sepsis physiopathology
Subjects
Details
- Language :
- English
- ISSN :
- 2211-1247
- Volume :
- 24
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cell reports
- Publication Type :
- Academic Journal
- Accession number :
- 29996098
- Full Text :
- https://doi.org/10.1016/j.celrep.2018.06.026