PMID- 35686918
OWN - NLM
STAT- MEDLINE
DCOM- 20230203
LR  - 20230314
IS  - 1462-0332 (Electronic)
IS  - 1462-0324 (Linking)
VI  - 62
IP  - 2
DP  - 2023 Feb 1
TI  - DNA from macrophages induces fibrosis and vasculopathy through POLR3A/STING/type 
      I interferon axis in systemic sclerosis.
PG  - 934-945
LID - 10.1093/rheumatology/keac324 [doi]
AB  - OBJECTIVE: To clarify the role of RNA polymerase III A (POLR3A)/type I IFN in the 
      pathogenesis of SSc. METHODS: Cytosolic DNA and stimulator of IFN genes (STING) 
      pathway in skin or serum of SSc patients were detected by immunofluorescence, 
      immunohistochemistry and western blotting. DNA from human macrophages was 
      transfected to SSc fibroblasts or human umbilical vein endothelial cells (HUVECs) 
      and then markers of POLR3A/STING pathway were detected by real-time qPCR, western 
      blotting and confocal microscopy. After H151 treatment or knocking down 
      POLR3A/STING, type I IFN response, monocytes adhesion and activation of 
      fibroblasts and HUVECs were evaluated. Regulation of IFN regulatory factor 3 
      (IRF3) on monocyte chemoattractant protein-1 (MCP-1) was determined by chromatin 
      immunoprecipitation. In bleomycin (BLM)-induced SSc mice, the effect of STING 
      knockout or H151 on vasculopathy and fibrosis was assessed. RESULTS: Cytosolic 
      DNA, colocalization of STING with alpha-smooth muscle actin (alpha-SMA) or CD31 in 
      the skin, and STING pathway in the serum of SSc patients were increased. 
      Macrophage-derived DNA stimulated the translocation of POLR3A from nucleus to the 
      perinuclear region near STING and activated POLR3A/STING/type I IFN response, 
      monocytes adhesion and MCP-1 expression in fibroblasts/HUVECs and collagen 
      overproduction of fibroblasts. The activated IRF3 bound to the promoter of MCP-1. 
      STING deficiency or H151 administration ameliorated fibrosis and vasculopathy 
      both in vitro and in BLM-induced SSc mice. CONCLUSIONS: SSc presented increased 
      DNA leakage and STING pathway activation. DNA from macrophages induced type I IFN 
      signature of fibroblasts and ECs through POLR3A/STING pathway. Blocking 
      POLR3A/STING axis provides a new therapeutic target for SSc.
CI  - (c) The Author(s) 2022. Published by Oxford University Press on behalf of the 
      British Society for Rheumatology. All rights reserved. For permissions, please 
      email: journals.permissions@oup.com.
FAU - Liu, Chaofan
AU  - Liu C
AD  - Department of Dermatology.
FAU - Tang, Jiaxuan
AU  - Tang J
AD  - Department of Dermatology.
FAU - Luo, Wei
AU  - Luo W
AD  - Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, 
      Zhongshan Hospital, Fudan University, Shanghai, China.
FAU - Liu, Shiying
AU  - Liu S
AD  - Department of Dermatology.
FAU - Sun, Xiaolei
AU  - Sun X
AD  - Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, 
      Zhongshan Hospital, Fudan University, Shanghai, China.
FAU - Hong, Wenxuan
AU  - Hong W
AD  - Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, 
      Zhongshan Hospital, Fudan University, Shanghai, China.
FAU - Zhou, Xing
AU  - Zhou X
AD  - Department of Dermatology.
FAU - Lu, Jinghao
AU  - Lu J
AD  - Department of Dermatology.
FAU - Li, Ming
AU  - Li M
AD  - Department of Dermatology.
FAU - Zhu, Lubing
AU  - Zhu L
AD  - Department of Dermatology.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Rheumatology (Oxford)
JT  - Rheumatology (Oxford, England)
JID - 100883501
RN  - 9007-49-2 (DNA)
RN  - EC 2.7.7.6 (POLR3A protein, human)
RN  - EC 2.7.7.6 (RNA Polymerase III)
SB  - IM
MH  - Humans
MH  - Mice
MH  - Animals
MH  - *Scleroderma, Systemic/pathology
MH  - Fibrosis
MH  - Human Umbilical Vein Endothelial Cells/metabolism/pathology
MH  - Macrophages/metabolism
MH  - DNA
MH  - Fibroblasts/metabolism
MH  - Skin/pathology
MH  - RNA Polymerase III
OTO - NOTNLM
OT  - RNA polymerase III A
OT  - SSc
OT  - STING
OT  - cytosolic DNA
OT  - endothelial cell
OT  - fibroblast
OT  - fibrosis
OT  - type I interferon
OT  - vasculopathy
EDAT- 2022/06/11 06:00
MHDA- 2023/02/04 06:00
CRDT- 2022/06/10 09:13
PHST- 2022/02/22 00:00 [received]
PHST- 2022/05/20 00:00 [revised]
PHST- 2022/06/11 06:00 [pubmed]
PHST- 2023/02/04 06:00 [medline]
PHST- 2022/06/10 09:13 [entrez]
AID - 6605220 [pii]
AID - 10.1093/rheumatology/keac324 [doi]
PST - ppublish
SO  - Rheumatology (Oxford). 2023 Feb 1;62(2):934-945. doi: 
      10.1093/rheumatology/keac324.