Faculty Collaboration Database

Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation. Immunity 2021 Jul 13;54(7):1463-1477.e11

Date

06/12/2021

Pubmed ID

34115964

Pubmed Central ID

PMC8189765

DOI

10.1016/j.immuni.2021.05.004

Scopus ID

2-s2.0-85107723500 (requires institutional sign-in at Scopus site)   312 Citations

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.

Author List

Xian H, Liu Y, Rundberg Nilsson A, Gatchalian R, Crother TR, Tourtellotte WG, Zhang Y, Aleman-Muench GR, Lewis G, Chen W, Kang S, Luevanos M, Trudler D, Lipton SA, Soroosh P, Teijaro J, de la Torre JC, Arditi M, Karin M, Sanchez-Lopez E

Author

Hongxu Xian PhD Assistant Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenosine Triphosphate
Animals
Cytokines
DNA, Mitochondrial
Humans
Inflammasomes
Interleukin-1beta
Lipopolysaccharides
Metformin
Mice
NLR Family, Pyrin Domain-Containing 3 Protein
Nucleoside-Phosphate Kinase
Pneumonia