PMID- 36106559
OWN - NLM
STAT- MEDLINE
DCOM- 20221205
LR  - 20221205
IS  - 1365-2184 (Electronic)
IS  - 0960-7722 (Print)
IS  - 0960-7722 (Linking)
VI  - 55
IP  - 12
DP  - 2022 Dec
TI  - Mitochondrial DNA mediates immunoparalysis of dendritic cells in sepsis via STING 
      signalling.
PG  - e13328
LID - 10.1111/cpr.13328 [doi]
LID - e13328
AB  - BACKGROUND: Mitochondrial DNA (mtDNA) is a potent activator for pro-inflammatory 
      response. Dendritic cells (DCs) are immunosuppressed in sepsis, whether mtDNA 
      mediates immunoparalysis in sepsis remains unknown. METHODS: The mRNAs were 
      assessed by qPCR. Flow cytometry was used to measure the expression of 
      costimulatory molecules and the proliferation of CD4(+) T cells. Western blot and 
      immunofluorescence staining were used to analyse the expression of proteins. 
      Cytokine secretion was detected by ELISA. Histology of lung tissue was used to 
      assess the inflammatory injury. RESULTS: Lipopolysaccharide-induced endotoxemia 
      increased plasma mtDNA levels and immunoparalysis of spleen DCs, while 
      hydrolysing mtDNA reversed immunoparalysis of spleen DCs in vivo. Moreover, 
      cytoplasmic mtDNA of DCs was accumulated in endotoxemia and sepsis. mtDNA 
      transfection into bone marrow-derived DCs (BMDCs) inhibited the expression of 
      costimulatory molecules (e.g., CD40, CD80 and CD86) and the release of IL-12p70, 
      while increasing the secretion of IL-10. Cytoplasmic mtDNA also inhibited the 
      ability of BMDCs to promote the proliferation of CD4(+) T cells. Mechanistic 
      analysis revealed that STING signalling was required for mtDNA-mediated 
      immunoparalysis of DCs in vivo and in vitro. Further studies showed deletion of 
      STING reversed mtDNA-mediated immunoparalysis of DCs and improved the prognosis 
      of endotoxemia and sepsis. CONCLUSION: Our results demonstrated that mtDNA 
      promotes immunoparalysis of DCs, and contributes to sepsis-associated 
      immunosuppression by activating STING signalling. Our study may provide new 
      insights to elucidate the molecular pathogenesis of immunosuppressive DCs in 
      sepsis.
CI  - (c) 2022 The Authors. Cell Proliferation published by European Cell Proliferation 
      Society and John Wiley & Sons Ltd.
FAU - Tu, Qing
AU  - Tu Q
AD  - Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong 
      University School of Medicine, Shanghai, China.
FAU - Li, Yi
AU  - Li Y
AUID- ORCID: 0000-0003-3245-9724
AD  - Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong 
      University School of Medicine, Shanghai, China.
FAU - Zhu, Jiali
AU  - Zhu J
AD  - Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong 
      University School of Medicine, Shanghai, China.
FAU - Guo, Long
AU  - Guo L
AD  - Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong 
      University School of Medicine, Shanghai, China.
FAU - Liu, Chenchen
AU  - Liu C
AD  - School of Anesthesiology, Weifang Medical University, Weifang, China.
FAU - Liu, Lu
AU  - Liu L
AD  - School of Anesthesiology, Weifang Medical University, Weifang, China.
FAU - Yuan, Yuan
AU  - Yuan Y
AD  - Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong 
      University School of Medicine, Shanghai, China.
FAU - Zou, Yun
AU  - Zou Y
AD  - Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong 
      University School of Medicine, Shanghai, China.
FAU - Chen, Feng
AU  - Chen F
AD  - Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong 
      University School of Medicine, Shanghai, China.
FAU - Yao, Liangfang
AU  - Yao L
AD  - Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong 
      University School of Medicine, Shanghai, China.
FAU - Li, Jinbao
AU  - Li J
AUID- ORCID: 0000-0001-5582-5737
AD  - Department of Anesthesiology, Shanghai General Hospital, Shanghai Jiao Tong 
      University School of Medicine, Shanghai, China.
LA  - eng
GR  - 81701943/National Natural Science Foundation of China/
GR  - 81971813/National Natural Science Foundation of China/
PT  - Journal Article
DEP - 20220915
PL  - England
TA  - Cell Prolif
JT  - Cell proliferation
JID - 9105195
RN  - 0 (DNA, Mitochondrial)
SB  - IM
MH  - Humans
MH  - Dendritic Cells/metabolism
MH  - DNA, Mitochondrial/genetics/metabolism
MH  - *Endotoxemia/metabolism
MH  - Spleen
MH  - *Sepsis
PMC - PMC9715356
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/09/16 06:00
MHDA- 2022/12/06 06:00
PMCR- 2022/09/15
CRDT- 2022/09/15 05:03
PHST- 2022/07/09 00:00 [revised]
PHST- 2022/02/16 00:00 [received]
PHST- 2022/08/06 00:00 [accepted]
PHST- 2022/09/16 06:00 [pubmed]
PHST- 2022/12/06 06:00 [medline]
PHST- 2022/09/15 05:03 [entrez]
PHST- 2022/09/15 00:00 [pmc-release]
AID - CPR13328 [pii]
AID - 10.1111/cpr.13328 [doi]
PST - ppublish
SO  - Cell Prolif. 2022 Dec;55(12):e13328. doi: 10.1111/cpr.13328. Epub 2022 Sep 15.