The antidiabetic drug metformin blunts NETosis in vitro and reduces circulating NETosis biomarkers in vivo

Menegazzo, Lisa; Scattolini, Valentina; Cappellari, Roberta; Bonora, Benedetta Maria; Albiero, Mattia; Bortolozzi, Mario; Romanato, Filippo; Ceolotto, Giulio; Kreutzeberg, Saula Vigili de; Avogaro, Angelo; Fadini, Gian Paolo

doi:10.1007/s00592-018-1129-8

Cited by 120 publications

(102 citation statements)

References 27 publications

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“…Additionally, NET formation, nucleosome, and NE-dsDNA complexes were still present in the plasma of patients after 6 months of metformin treatment, while all neutrophil functional responses returned to normal values after 12 months with no change in neutrophil count across this period [57]. This finding about metformin was later investigated by Menegazzo et al confirming that metformin reduced NE, PR3, histones, and dsDNA levels [58]. Indeed, metformin blocked in vitro pathologic changes in nuclear dynamics and DNA release provoking a blunted NETosis in response to classical NET stimuli [58].…”

Section: Nets In Diabetesmentioning

confidence: 82%

“…This finding about metformin was later investigated by Menegazzo et al confirming that metformin reduced NE, PR3, histones, and dsDNA levels [58]. Indeed, metformin blocked in vitro pathologic changes in nuclear dynamics and DNA release provoking a blunted NETosis in response to classical NET stimuli [58]. As NET formation is likely to be associated with glucose-stimulated reactive oxygen species (ROS) production, it is possible that ROS have a direct effect on NET production.…”

Section: Nets In Diabetesmentioning

confidence: 92%

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Neutrophil Extracellular Traps and Cardiovascular Diseases: An Update

Bonaventura

Vecchiè

Abbate

et al. 2020

Cells

129

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Neutrophil extracellular traps (NETs) are formed by decondensed chromatin, histones, and neutrophil granular proteins and have a role in entrapping microbial pathogens. NETs, however, have pro-thrombotic properties by stimulating fibrin deposition, and increased NET levels correlate with larger infarct size and predict major adverse cardiovascular (CV) events. NETs have been involved also in the pathogenesis of diabetes, as high glucose levels were found to induce NETosis. Accordingly, NETs have been described as drivers of diabetic complications, such as diabetic wound and diabetic retinopathy. Inflammasomes are macromolecular structures involved in the release of pro-inflammatory mediators, such as interleukin-1, which is a key mediator in CV diseases. A crosstalk between the inflammasome and NETs is known for some rheumatologic diseases, while this link is still under investigation and not completely understood in CV diseases. In this review, we summarized the most recent updates about the role of NETs in acute myocardial infarction and metabolic diseases and provided an overview on the relationship between NET and inflammasome activities in rheumatologic diseases, speculating a possible link between these two entities also in CV diseases.

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Section: Nets In Diabetesmentioning

confidence: 82%

Section: Nets In Diabetesmentioning

confidence: 92%

Neutrophil Extracellular Traps and Cardiovascular Diseases: An Update

Bonaventura

Vecchiè

Abbate

et al. 2020

Cells

129

View full text Add to dashboard Cite

show abstract

“…For example, metformin inhibits the expression of IL-1β, IL-6, and TNFα by activated macrophages (33,(35)(36)(37) but enhances their IL-10 expression (38). Metformin also reduces the release of NETs from neutrophils in patients with diabetes (39,40). Furthermore, treatment of mice with metformin results in a reduction in the cytokine production of Th1 and Th17 cells and their infiltration in the central nervous system, slowing the disease progression of experimental autoimmune encephalomyelitis (41).…”

Section: Metformin Inhibits Inflammatory Responses and Alleviates Acumentioning

confidence: 99%

Immunomodulatory and Antiviral Activity of Metformin and Its Potential Implications in Treating Coronavirus Disease 2019 and Lung Injury

et al. 2020

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The pandemic of coronavirus disease 2019 (COVID-19), a disease which causes severe lung injury and multiple organ damage, presents an urgent need for new drugs. The case severity and fatality of COVID-19 are associated with excessive inflammation, namely, a cytokine storm. Metformin, a widely used drug to treat type 2 diabetes (T2D) mellitus and metabolic syndrome, has immunomodulatory activity that reduces the production of proinflammatory cytokines using macrophages and causes the formation of neutrophil extracellular traps (NETs). Metformin also inhibits the cytokine production of pathogenic Th1 and Th17 cells. Importantly, treatment with metformin alleviates various lung injuries in preclinical animal models. In addition, a recent proteomic study revealed that metformin has the potential to directly inhibit SARS-CoV-2 infection. Furthermore, retrospective clinical studies have revealed that metformin treatment reduces the mortality of T2D with COVID-19. Therefore, metformin has the potential to be repurposed to treat patients with COVID-19 at risk of developing severe illness. This review summarizes the immune pathogenesis of SARS-CoV-2 and addresses the effects of metformin on inhibiting cytokine storms and preventing SARS-CoV-2 infection, as well as its side effects.

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“…NETosis can be experimentally induced in vitro following exposure of human peripheral blood white cells to high glucose concentration ( 113 ); similarly, exaggerated NETosis has been clearly demonstrated in patients with T2D ( 113 , 114 ), and this process can be restored by treatment with metformin ( 115 ). Finally, in patients with pre-diabetes, metformin treatment reduces the concentration of NET components independently from glycemic control ( 116 ).…”

Section: Effects Of Metformin On Immune Cells Involved In Autoimmune mentioning

confidence: 99%

Metformin and Autoimmunity: A “New Deal” of an Old Drug

et al. 2018

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Metformin (dimethyl biguanide) is a synthetic derivative of guanidine, isolated from the extracts of Galega officinalis, a plant with a prominent antidiabetic effect. Since its discovery more than 50 years ago, metformin represents a worldwide milestone in treatment of patients with type 2 diabetes (T2D). Recent evidence in humans indicates novel pleiotropic actions of metformin which span from its consolidated role in T2D management up to various regulatory properties, including cardio- and nephro-protection, as well as antiproliferative, antifibrotic, and antioxidant effects. These findings, together with ground-breaking studies demonstrating its ability to prolong healthspan and lifespan in mice, provided the basis for defining metformin as a potential antiaging molecule. Moreover, emerging in vivo and in vitro evidence support the novel hypothesis that metformin can exhibit immune-modulatory features. Studies suggest that metformin interferes with key immunopathological mechanisms involved in systemic autoimmune diseases, such as the T helper 17/regulatory T cell balance, germinal centers formation, autoantibodies production, macrophage polarization, cytokine synthesis, neutrophil extracellular traps release, and bone or extracellular matrix remodeling. These effects may represent a powerful contributor to antiaging and anticancer properties exerted by metformin and, from another standpoint, may open the way to assess whether metformin can be a candidate molecule for clinical trials involving patients with immune-mediated diseases. In this article, we will review the available preclinical and clinical evidence regarding the effect of metformin on individual cells of the immune system, with emphasis on immunological mechanisms related to the development and maintenance of autoimmunity and its potential relevance in treatment of autoimmune diseases.

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The antidiabetic drug metformin blunts NETosis in vitro and reduces circulating NETosis biomarkers in vivo

Abstract: Metformin treatment reduced the concentrations of NET components independently from glucose control. This effect was reproducible in vitro and was related to the inhibitory effect exerted by metformin on the PKC-NADPH oxidase pathway.

Cited by 120 publications

References 27 publications

Neutrophil Extracellular Traps and Cardiovascular Diseases: An Update

Neutrophil Extracellular Traps and Cardiovascular Diseases: An Update

Immunomodulatory and Antiviral Activity of Metformin and Its Potential Implications in Treating Coronavirus Disease 2019 and Lung Injury

Metformin and Autoimmunity: A “New Deal” of an Old Drug

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