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Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation

Xian, Hongxu ; Liu, Yuan ; Rundberg Nilsson, Alexandra LU ; Gatchalian, Raphaella ; Crother, Timothy R ; Tourtellotte, Warren G ; Zhang, Yi ; Aleman-Muench, German R ; Lewis, Gavin and Chen, Weixuan , et al. (2021) In Immunity 54(7). p.1463-1477
Abstract

Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1β production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase... (More)

Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1β production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.

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type
Contribution to journal
publication status
published
subject
keywords
Adenosine Triphosphate/metabolism, Animals, COVID-19/metabolism, Cytokines/genetics, DNA, Mitochondrial/biosynthesis, Humans, Inflammasomes/drug effects, Interleukin-1beta/genetics, Lipopolysaccharides/toxicity, Metformin/pharmacology, Mice, NLR Family, Pyrin Domain-Containing 3 Protein/metabolism, Nucleoside-Phosphate Kinase/metabolism, Pneumonia/metabolism, Respiratory Distress Syndrome/chemically induced, SARS-CoV-2/pathogenicity
in
Immunity
volume
54
issue
7
article number
e11
pages
1463 - 1477
publisher
Cell Press
external identifiers
  • pmid:34115964
  • scopus:85107723500
ISSN
1074-7613
DOI
10.1016/j.immuni.2021.05.004
language
English
LU publication?
no
additional info
Copyright © 2021 Elsevier Inc. All rights reserved.
id
89e0af70-d8d3-4427-b2dd-dfe930f34125
date added to LUP
2023-05-22 11:11:41
date last changed
2024-04-19 22:58:24
@article{89e0af70-d8d3-4427-b2dd-dfe930f34125,
  abstract     = {{<p>Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1β production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.</p>}},
  author       = {{Xian, Hongxu and Liu, Yuan and Rundberg Nilsson, Alexandra and Gatchalian, Raphaella and Crother, Timothy R and Tourtellotte, Warren G and Zhang, Yi and Aleman-Muench, German R and Lewis, Gavin and Chen, Weixuan and Kang, Sarah and Luevanos, Melissa and Trudler, Dorit and Lipton, Stuart A and Soroosh, Pejman and Teijaro, John and de la Torre, Juan Carlos and Arditi, Moshe and Karin, Michael and Sanchez-Lopez, Elsa}},
  issn         = {{1074-7613}},
  keywords     = {{Adenosine Triphosphate/metabolism; Animals; COVID-19/metabolism; Cytokines/genetics; DNA, Mitochondrial/biosynthesis; Humans; Inflammasomes/drug effects; Interleukin-1beta/genetics; Lipopolysaccharides/toxicity; Metformin/pharmacology; Mice; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism; Nucleoside-Phosphate Kinase/metabolism; Pneumonia/metabolism; Respiratory Distress Syndrome/chemically induced; SARS-CoV-2/pathogenicity}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{7}},
  pages        = {{1463--1477}},
  publisher    = {{Cell Press}},
  series       = {{Immunity}},
  title        = {{Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation}},
  url          = {{http://dx.doi.org/10.1016/j.immuni.2021.05.004}},
  doi          = {{10.1016/j.immuni.2021.05.004}},
  volume       = {{54}},
  year         = {{2021}},
}