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

Immunity
Hongxu XianElsa Sanchez-Lopez

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 (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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Citations

Aug 8, 2021·International Journal of Molecular Sciences·So Yeong Cheon, Bon-Nyeo Koo
Aug 11, 2021·Nature Reviews. Immunology·Setu M VoraHao Wu
Nov 19, 2021·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Maureen Yin, Luke A J O'Neill
Oct 2, 2021·The Journal of Pharmacology and Experimental Therapeutics·Robert N WilletteDean J Welsch

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