PMID- 36068919
OWN - NLM
STAT- MEDLINE
DCOM- 20230126
LR  - 20240105
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 31
IP  - 1
DP  - 2023 Jan 4
TI  - NLRC3 expression in macrophage impairs glycolysis and host immune defense by 
      modulating the NF-kappaB-NFAT5 complex during septic immunosuppression.
PG  - 154-173
LID - S1525-0016(22)00552-4 [pii]
LID - 10.1016/j.ymthe.2022.08.023 [doi]
AB  - Impairment of innate immune cell function and metabolism underlies 
      immunosuppression in sepsis; however, a promising therapy to orchestrate this 
      impairment is currently lacking. In this study, high levels of NOD-like receptor 
      family CARD domain containing-3 (NLRC3) correlated with the glycolytic defects of 
      monocytes/macrophages from septic patients and mice that developed 
      immunosuppression. Myeloid-specific NLRC3 deletion improved macrophage glycolysis 
      and sepsis-induced immunosuppression. Mechanistically, NLRC3 inhibits nuclear 
      factor (NF)-kappaB p65 binding to nuclear factor of activated T cells 5 (NFAT5), 
      which further controls the expression of glycolytic genes and proinflammatory 
      cytokines of immunosuppressive macrophages. This is achieved by decreasing NF-kappaB 
      activation-co-induced by TNF-receptor-associated factor 6 (TRAF6) or mammalian 
      target of rapamycin (mTOR)-and decreasing transcriptional co-activator p300 
      activity by inducing NLRC3 sequestration of mTOR and p300. Genetic inhibition of 
      NLRC3 disrupted the NLRC3-mTOR-p300 complex and enhanced NF-kappaB binding to the 
      NFAT5 promoter in concert with p300. Furthermore, intrapulmonary delivery of 
      recombinant adeno-associated virus harboring a macrophage-specific NLRC3 deletion 
      vector significantly improved the defense of septic mice that developed 
      immunosuppression upon secondary intratracheal bacterial challenge. Collectively, 
      these findings indicate that NLRC3 mediates critical aspects of innate immunity 
      that contribute to an immunocompromised state during sepsis and identify 
      potential therapeutic targets.
CI  - Copyright (c) 2022 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Xu, Jiqian
AU  - Xu J
AD  - Department of Critical Care Medicine, Union Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430022, China; Institute of 
      Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical 
      College, Huazhong University of Science and Technology, Wuhan 430022, China.
FAU - Gao, Chenggang
AU  - Gao C
AD  - Department of Critical Care Medicine, Union Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430022, China.
FAU - He, Yajun
AU  - He Y
AD  - Department of Critical Care Medicine, Union Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430022, China.
FAU - Fang, Xiangzhi
AU  - Fang X
AD  - Department of Critical Care Medicine, Union Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430022, China.
FAU - Sun, Deyi
AU  - Sun D
AD  - Department of Critical Care Medicine, Union Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430022, China.
FAU - Peng, Zhekang
AU  - Peng Z
AD  - Department of Critical Care Medicine, Union Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430022, China.
FAU - Xiao, Hairong
AU  - Xiao H
AD  - Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, Wuhan 430022, 
      China.
FAU - Sun, Miaomiao
AU  - Sun M
AD  - Department of Critical Care Medicine, Union Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430022, China.
FAU - Zhang, Pei
AU  - Zhang P
AD  - Department of Paediatrics, Jinling Hospital, School of Medicine, Nanjing 
      University, Nanjing 210016, China.
FAU - Zhou, Ting
AU  - Zhou T
AD  - Department of Critical Care Medicine, Union Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430022, China.
FAU - Yang, Xiaobo
AU  - Yang X
AD  - Department of Critical Care Medicine, Union Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430022, China.
FAU - Yu, Yuan
AU  - Yu Y
AD  - Department of Critical Care Medicine, Union Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430022, China.
FAU - Li, Ruiting
AU  - Li R
AD  - Department of Critical Care Medicine, Union Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430022, China.
FAU - Zou, Xiaojing
AU  - Zou X
AD  - Department of Critical Care Medicine, Union Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430022, China.
FAU - Shu, Huaqing
AU  - Shu H
AD  - Department of Critical Care Medicine, Union Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430022, China.
FAU - Qiu, Yang
AU  - Qiu Y
AD  - State Key Laboratory of Virology, Center for Biosafety Mega-Science, Chinese 
      Academy of Sciences, Wuhan Institute of Virology, Wuhan 43007, China.
FAU - Zhou, Xi
AU  - Zhou X
AD  - State Key Laboratory of Virology, Center for Biosafety Mega-Science, Chinese 
      Academy of Sciences, Wuhan Institute of Virology, Wuhan 43007, China.
FAU - Yuan, Shiying
AU  - Yuan S
AD  - Department of Critical Care Medicine, Union Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430022, China; Institute of 
      Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical 
      College, Huazhong University of Science and Technology, Wuhan 430022, China.
FAU - Yao, Shanglong
AU  - Yao S
AD  - Institute of Anesthesiology and Critical Care Medicine, Union Hospital, Tongji 
      Medical College, Huazhong University of Science and Technology, Wuhan 430022, 
      China.
FAU - Shang, You
AU  - Shang Y
AD  - Department of Critical Care Medicine, Union Hospital, Tongji Medical College, 
      Huazhong University of Science and Technology, Wuhan 430022, China; Institute of 
      Anesthesiology and Critical Care Medicine, Union Hospital, Tongji Medical 
      College, Huazhong University of Science and Technology, Wuhan 430022, China. 
      Electronic address: you_shang@hust.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220906
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (NF-kappa B)
RN  - 0 (Nfat5 protein, mouse)
RN  - 0 (NLRC3 protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - 0 (Transcription Factors)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Intercellular Signaling Peptides and Proteins/metabolism
MH  - *Macrophages/immunology
MH  - *NF-kappa B/metabolism
MH  - *Sepsis/immunology/metabolism
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - *Transcription Factors/metabolism
MH  - *Immune Tolerance
MH  - Immunocompromised Host
PMC - PMC9840117
OTO - NOTNLM
OT  - NLRC3
OT  - gene therapy
OT  - host immune defense
OT  - immunometabolism
OT  - macrophages
OT  - sepsis-induced immunosuppression
COIS- Declaration of interests The authors declare that they have no competing 
      interests.
EDAT- 2022/09/08 06:00
MHDA- 2023/01/10 06:00
PMCR- 2024/01/04
CRDT- 2022/09/07 01:54
PHST- 2022/02/07 00:00 [received]
PHST- 2022/06/23 00:00 [revised]
PHST- 2022/08/30 00:00 [accepted]
PHST- 2022/09/08 06:00 [pubmed]
PHST- 2023/01/10 06:00 [medline]
PHST- 2022/09/07 01:54 [entrez]
PHST- 2024/01/04 00:00 [pmc-release]
AID - S1525-0016(22)00552-4 [pii]
AID - 10.1016/j.ymthe.2022.08.023 [doi]
PST - ppublish
SO  - Mol Ther. 2023 Jan 4;31(1):154-173. doi: 10.1016/j.ymthe.2022.08.023. Epub 2022 
      Sep 6.