Journal
IMMUNITY
Volume 54, Issue 7, Pages 1463-+Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2021.05.004
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Funding
- NCI Cancer Center Support Grant [CCSG P30CA23100]
- NIH [R01AI072726, R01NS095894, U54CA260591, R01A1043477, P42ES010337]
- NIAMS [K01AR077111]
- Resource-based Center for the study of the joint microenvironment in rheumatology UCSD [P30AR073761]
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The study found that metformin can attenuate COVID-19-induced ARDS by inhibiting NLRP3 inflammasome activation, IL-1 beta and IL-6 secretion, and by blocking ATP and mtDNA synthesis.
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)-1 beta 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-kappa B, 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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