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

Xian, Hongxu; Liu, Yuan; Rundberg Nilsson, Alexandra; Gatchalian, Raphaella; Crother, Timothy R.; Tourtellotte, Warren G.; Zhang, Yi; Aleman-Muench, German R.; Lewis, Gavin; Chen, Weixuan; Kang, Sarah; Luevanos, Melissa; Trudler, Dorit; Lipton, Stuart A.; Soroosh, Pejman; Teijaro, John; de la Torre, Juan Carlos; Arditi, Moshe; Karin, Michael; Sanchez-Lopez, Elsa

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.