Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice

Collotta, Debora; Hull, William M.; Mastrocola, Raffaella; Chiazza, Fausto; Cento, Alessia Sofia; Murphy, Catherine C.; Verta, Roberta; Alves, Gustavo Ferreira; Gaudioso, Giulia; Fava, Francesca; Yaqoob, Magdi; Aragno, Manuela; Tuohy, Kieran; Thiemermann, Christoph; Collino, Massimo

doi:10.1016/j.molmet.2020.101009

Cited by 26 publications

(25 citation statements)

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“…Experimental evidence for key roles of the JAK and BTK cascades in modulating expression of the NLRP3 inflammasome and diabesity pathogenesis has been published (Collotta et al, 2020;Furuya et al, 2018;Purvis et al, 2020).…”

Section: Jak and Bruton's Tk Inhibitorsmentioning

confidence: 99%

“…A study on baricitinib has already been concluded with interesting results (NCT04358614), and others are recruiting patients for both the treatments (baricitinib: NCT04320277 and NCT04390464; acalabrutinib: NCT04346199 and NCT04380688). Experimental evidence for key roles of the JAK and BTK cascades in modulating expression of the NLRP3 inflammasome and diabesity pathogenesis has been published (Collotta et al, 2020; Furuya et al, 2018; Purvis et al, 2020).…”

Section: The Nlrp3 Inflammasome and Pharmacological Treatments For Comentioning

confidence: 99%

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The hidden role of NLRP3 inflammasome in obesity‐related COVID‐19 exacerbations: Lessons for drug repurposing

Bertocchi

Foglietta

Collotta

et al. 2020

British J Pharmacology

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COVID-19, the illness caused by SARS-CoV-2, has a wide-ranging clinical spectrum that, in the worst-case scenario, involves a rapid progression to severe acute respiratory syndrome and death. Epidemiological data show that obesity and diabetes are among the main risk factors associated with high morbidity and mortality. The increased susceptibility to SARS-CoV-2 infection documented in obesity-related metabolic derangements argues for initial defects in defence mechanisms, most likely due to an elevated systemic metabolic inflammation ("metaflammation"). The NLRP3 inflammasome is a master regulator of metaflammation and has a pivotal role in the pathophysiology of either obesity or diabetes. Here, we discuss the most recent findings suggesting contribution of NLRP3 inflammasome to the increase in complications in COVID-19 patients with diabesity. We also review current pharmacological strategies for COVID-19, focusing on treatments whose efficacy could be due, at least in part, to interference with the activation of the NLRP3 inflammasome.

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Section: Jak and Bruton's Tk Inhibitorsmentioning

confidence: 99%

Section: The Nlrp3 Inflammasome and Pharmacological Treatments For Comentioning

confidence: 99%

The hidden role of NLRP3 inflammasome in obesity‐related COVID‐19 exacerbations: Lessons for drug repurposing

Bertocchi

Foglietta

Collotta

et al. 2020

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Accumulated evidence from animal studies has suggested a substantial pathogenic role of the JAK/STAT pathways in the development of low-grade chronic inﬂammatory response contributing to obesity and type II DM[ 175 - 177 ]. Notably, in a type II diabetic rat model induced by fructose/streptozotocin administration, treating with TOF alone, despite more potent efficacy in combination with aspirin to inhibit the NF-κB signaling, could lower serum proinflammatory cytokine expressions and skeletal muscle SOCS-3 Levels, resulting in reduced IR with decreased blood glucose and HOMA-IR levels and improved β-cell function with increased serum insulin and HOMA-β levels[ 176 ].…”

Section: Role Of Il-1 In Irmentioning

confidence: 99%

“…Notably, in addition to the involvement in cytokine signaling activation, the JAKs/STATs pathway has been shown to regulate the function and survival of pancreatic β-cells[ 215 , 216 ]. Notably, animal studies have implicated targeting such a pathway in reducing IR and treating type II diabetes[ 175 - 177 ]. In human trials, the diabetic treatment intensification in RA combined with DM comorbidity was lowest in patients under the 9 mo TOF treatment[ 178 ].…”

Section: Role Of Il-1 In Irmentioning

confidence: 99%

Anti- and non-tumor necrosis factor-α-targeted therapies effects on insulin resistance in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis

Wang¹,

Tsai²

2021

WJD

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In addition to β-cell failure with inadequate insulin secretion, the crucial mechanism leading to establishment of diabetes mellitus (DM) is the resistance of target cells to insulin, i.e . insulin resistance (IR), indicating a requirement of beyond-normal insulin concentrations to maintain euglycemic status and an ineffective strength of transduction signaling from the receptor, downstream to the substrates of insulin action. IR is a common feature of most metabolic disorders, particularly type II DM as well as some cases of type I DM. A variety of human inﬂammatory disorders with increased levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β, have been reported to be associated with an increased risk of IR. Autoimmune-mediated arthritis conditions, including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), with the involvement of proinflammatory cytokines as their central pathogenesis, have been demonstrated to be associated with IR, especially during the active disease state. There is an increasing trend towards using biologic agents and small molecule-targeted drugs to treat such disorders. In this review, we focus on the effects of anti-TNF-α- and non-TNF-α-targeted therapies on IR in patients with RA, PsA and AS. Anti-TNF-α therapy, IL-1 blockade, IL-6 antagonist, Janus kinase inhibitor and phospho-diesterase type 4 blocker can reduce IR and improve diabetic hyper-glycemia in autoimmune-mediated arthritis.

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“…A study on baricitinib has already been concluded with interesting results (NCT04358614) and others are recruiting patients for both the treatments (Baricitinib: NCT04320277 and NCT04390464; Acalabrutinib: NCT04346199 and NCT04380688). Experimental evidence for key roles of the JAK and BTK cascades in either activation of the NLRP3 inflammasome and diabesity pathogenesis have been reported in the literature (Collotta et al, 2020;Furuya et al, 2018) Up to nowadays six clinical trials (NCT04347980, NCT04325061, NCT04395105, NCT04344730, NCT04360876, NCT04327401), reported on clinicaltrials.gov are recruiting patients to test the efficacy of the corticosteroid dexamethasone , whose beneficial effects in airway inflammation has been recently demonstrated to involve lung inhibition of the activity of NLRP3 inflammasome and the release of IL-1β and IL-18 (Guan, Ma, Fan, Chen, Miao & Wu, 2020).…”

Section: Immunosuppressantsmentioning

confidence: 99%

The hidden role of NLRP3 inflammasome in diabesity-related COVID-19 exacerbations: lessons for drug repurposing

Bertocchi

Foglietta

Collotta

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

COVID-19, the illness caused by SARS-CoV-2, has a wide-ranging clinical spectrum that, in the worst-case scenario, involves a rapid progression to severe acute respiratory syndrome and even death. Epidemiological data show that "diabesity", the association of obesity and diabetes, is among the main risk factors associated with high morbidity and mortality. The increased susceptibility to SARS-CoV-2 infection documented in diabesity argues for initial defects in defense mechanisms, most likely due to an elevated systemic metabolic inflammation ("metaflammation"). The NLRP3 inflammasome is a master regulator of metaflammation and has a pivotal role in the pathophysiology of diabesity. Here we discuss the most recent findings suggesting contribution of NLRP3 inflammasome to the increase in complications in COVID-19 patients with diabesity. We also review current pharmacological strategies for COVID-19, focusing on treatments whose efficacy could be due, at least in part, to interference with the activation of the NLRP3 inflammasome.

show abstract

Baricitinib counteracts metaflammation, thus protecting against diet-induced metabolic abnormalities in mice

Cited by 26 publications

References 50 publications

The hidden role of NLRP3 inflammasome in obesity‐related COVID‐19 exacerbations: Lessons for drug repurposing

The hidden role of NLRP3 inflammasome in obesity‐related COVID‐19 exacerbations: Lessons for drug repurposing

Anti- and non-tumor necrosis factor-α-targeted therapies effects on insulin resistance in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis

The hidden role of NLRP3 inflammasome in diabesity-related COVID-19 exacerbations: lessons for drug repurposing

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