Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation
(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.
(Less)
- author
- publishing date
- 2021-07-13
- 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
- 2024-08-11 08:13:35
@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}}, }