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

Xian, Hongxu; Liu, Yuan; Nilsson, Arne A.; Gatchalian, Raphaella; Crother, Timothy R.; Tourtellotte, Warren G.; Zhang, Yi; Alemán-Muench, Germán Rodrigo; Lewis, Gavin; Chen, Weixuan; Kang, Sarah M.; Luevanos, Melissa; Trudler, Dorit; Lipton, Stuart A.; Soroosh, Pejman; Teijaro, John R.; Torre, Juan Carlos de la; Arditi, Moshe; Karin, Michael; Sánchez-López, Elsa

doi:10.1016/j.immuni.2021.05.004

Cited by 231 publications

(184 citation statements)

References 96 publications

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“…The diabetes drug metformin indirectly inhibits NLRP3 by regulating mTOR, and its use is significantly associated with reduced mortality among patients with COVID-19 and type 2 diabetes. Metformin was also recently shown to inhibit NLRP3 activation and lung inflammation in SARS-CoV-2-infected mice 164 , 165 .…”

Section: Clinical Interventionsmentioning

confidence: 99%

Inflammasome activation at the crux of severe COVID-19

2021

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The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), results in life-threatening disease in a minority of patients, especially elderly people and those with co-morbidities such as obesity and diabetes. Severe disease is characterized by dysregulated cytokine release, pneumonia and acute lung injury, which can rapidly progress to acute respiratory distress syndrome, disseminated intravascular coagulation, multisystem failure and death. However, a mechanistic understanding of COVID-19 progression remains unclear. Here we review evidence that SARS-CoV-2 directly or indirectly activates inflammasomes, which are large multiprotein assemblies that are broadly responsive to pathogen-associated and stress-associated cellular insults, leading to secretion of the pleiotropic IL-1 family cytokines (IL-1β and IL-18), and pyroptosis, an inflammatory form of cell death. We further discuss potential mechanisms of inflammasome activation and clinical efforts currently under way to suppress inflammation to prevent or ameliorate severe COVID-19.

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Section: Clinical Interventionsmentioning

confidence: 99%

Inflammasome activation at the crux of severe COVID-19

2021

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“…Our study is limited to a single in vitro measure of metformin as a therapeutic for COVID-19, so a great deal of further study is necessary in order to establish this drug as a viable treatment. To this end, one recent study demonstrated metformin as efficacious in preventing acute respiratory distress syndrome in a preclinical animal model of COVID-19 ( 97 ). Therefore, although metformin is most likely to be useful as an adjuvant rather than front-line therapy for severe acute COVID-19, it remains an attractive option for targeting hyperinflammation in this disease to limit severity and mortality.…”

Section: Discussionmentioning

confidence: 99%

Metformin Suppresses Monocyte Immunometabolic Activation by SARS-CoV-2 Spike Protein Subunit 1

et al. 2021

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A hallmark of COVID-19 is a hyperinflammatory state associated with severity. Monocytes undergo metabolic reprogramming and produce inflammatory cytokines when stimulated with SARS-CoV-2. We hypothesized that binding by the viral spike protein mediates this effect, and that drugs which regulate immunometabolism could inhibit the inflammatory response. Monocytes stimulated with recombinant SARS-CoV-2 spike protein subunit 1 showed a dose-dependent increase in glycolytic metabolism associated with production of pro-inflammatory cytokines. This response was dependent on hypoxia-inducible factor-1α, as chetomin inhibited glycolysis and cytokine production. Inhibition of glycolytic metabolism by 2-deoxyglucose (2-DG) or glucose deprivation also inhibited the glycolytic response, and 2-DG strongly suppressed cytokine production. Glucose-deprived monocytes rescued cytokine production by upregulating oxidative phosphorylation, an effect which was not present in 2-DG-treated monocytes due to the known effect of 2-DG on suppressing mitochondrial metabolism. Finally, pre-treatment of monocytes with metformin strongly suppressed spike protein-mediated cytokine production and metabolic reprogramming. Likewise, metformin pre-treatment blocked cytokine induction by SARS-CoV-2 strain WA1/2020 in direct infection experiments. In summary, the SARS-CoV-2 spike protein induces a pro-inflammatory immunometabolic response in monocytes that can be suppressed by metformin, and metformin likewise suppresses inflammatory responses to live SARS-CoV-2. This has potential implications for the treatment of hyperinflammation during COVID-19.

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“…Xian et al demonstrated in mouse models, the anti-inflammatory role of metformin via inhibition of the NLRP3 inflammasome and interlekin-1β induced acute respiratory distress syndrome in SARS-CoV-2 infection. [30] Similarly statins such as simvastatin and lovastatin were found to be most effective in severe SARS-CoV-2 infection exerting its influence via cytotoxic T lymphocytes and regulatory T cell induction. [31] As the literature assessing the effect of medications targeting dysglycemia, hypertension, thrombosis, [32] and hypercholesterolemia on SARS-CoV-2 infection and severity tends to suggest modest protection against infection and mortality, future studies will be enhanced by accounting for medications to avoid negative confounding towards the null (eg, weaker associations due to the protective effect of medications being more common among patients with vs. without diabetes).…”

Section: Confoundingmentioning

confidence: 99%