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

  • Author(s): 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
  • et al.
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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