Targeting the NLRP3 inflammasome to Reduce Diet-induced Metabolic Abnormalities in Mice

Chiazza, Fausto; Couturier-Maillard, Aurélie; Benetti, Elisa; Mastrocola, Raffaella; Nigro, Debora; Cutrìn, Juan Carlos; Serpe, Loredana; Aragno, Manuela; Fantozzi, Roberto; Ryffel, Bernard; Thiemermann, Christoph; Collino, Massimo

doi:10.2119/molmed.2015.00104

Cited by 58 publications

(52 citation statements)

References 47 publications

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“…Our data demonstrate that the activation of ERK/Akt/GSK-3 β signaling is further enhanced by pharmacological inhibition of the NLRP3 inflammasome complex and this effect may significantly contribute to its cardioprotective effects. These data confirm our previous findings, showing that pharmacological inhibition of NLRP3 inflammasome significantly potentiates the activity of the prosurvival Akt pathway [31]. Besides, the cross-talk between NLRP3 inflammasome and RISK pathways is further confirmed by the comparative analysis of the expression/activity of members of both pathways, which show robust increase only in the 60 min reperfusion model in both cases.…”

Section: Discussionsupporting

confidence: 91%

Pharmacological Inhibition of NLRP3 Inflammasome Attenuates Myocardial Ischemia/Reperfusion Injury by Activation of RISK and Mitochondrial Pathways

Mastrocola

Penna

Tullio

et al. 2016

Oxidative Medicine and Cellular Longevity

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115

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Although the nucleotide-binding oligomerization domain- (NOD-) like receptor pyrin domain containing 3 (NLRP3) inflammasome has been recently detected in the heart, its role in cardiac ischemia/reperfusion (IR) is still controversial. Here, we investigate whether a pharmacological modulation of NLRP3 inflammasome exerted protective effects in an ex vivo model of IR injury. Isolated hearts from male Wistar rats (5-6 months old) underwent ischemia (30 min) followed by reperfusion (20 or 60 min) with and without pretreatment with the recently synthetized NLRP3 inflammasome inhibitor INF4E (50 μM, 20 min before ischemia). INF4E exerted protection against myocardial IR, shown by a significant reduction in infarct size and lactate dehydrogenase release and improvement in postischemic left ventricular pressure. The formation of the NLRP3 inflammasome complex was induced by myocardial IR and attenuated by INF4E in a time-dependent way. Interestingly, the hearts of the INF4E-pretreated animals displayed a marked improvement of the protective RISK pathway and this effect was associated increase in expression of markers of mitochondrial oxidative phosphorylation. Our results demonstrate for the first time that INF4E protected against the IR-induced myocardial injury and dysfunction, by a mechanism that involves inhibition of the NLRP3 inflammasome, resulting in the activation of the prosurvival RISK pathway and improvement in mitochondrial function.

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Section: Discussionsupporting

confidence: 91%

Pharmacological Inhibition of NLRP3 Inflammasome Attenuates Myocardial Ischemia/Reperfusion Injury by Activation of RISK and Mitochondrial Pathways

Mastrocola

Penna

Tullio

et al. 2016

Oxidative Medicine and Cellular Longevity

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115

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“…Inflammation has been implicated in the pathogenesis of diabetes and is a major contributor to complications in the diabetic retina (Chiazza et al, 2015). Low grade inflammation causes the upregulation of endothelial cell adhesion molecules e.g.…”

Section: Discussionmentioning

confidence: 99%

miR15a regulates NLRP3 inflammasome proteins in the retinal vasculature

Curtiss

Liu

Steinle

2018

Experimental Eye Research

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We have previously published that miR15a can reduce inflammatory cytokines, which could be key to diabetic retinal pathology. In this work, we wanted to investigate whether miR15a altered NLR pyrin domain 3 (NLRP3) proteins. Whole retinal lysates from both miR15a overexpressing mice and endothelial cell specific miR15a/16 knockout mice were used to investigate protein levels of forkhead box protein O1 (Foxo1), NLRP3, cleaved caspase 1 and interleukin-1 beta (IL-1β). Primary human retinal endothelial cells (REC) were cultured in normal and high glucose followed by transfection with a miR15a mimic for protein analyses. MiR15a expression was verified by quantitative PCR, and a luciferase binding assay was used to examine whether miR15a directly bound Foxo1. In mouse retinal lysates, loss of miR15a increased Foxo1, IL-1β, NLRP3, and cleaved caspase 1 levels. REC grown in high glucose transfected with the miR15a mimic had decreased levels of Foxo1 and NLRP3. miR15a directly binds to Foxo1. miR15a regulates NLRP3 actions in the retinal vasculature. Work in mice showed that loss of miR15a increased NLRP3 pathway signaling and Foxo1. miR15a mimics decreased levels of Foxo1 and NLRP3. Taken together, miR15a reduced inflammasome proteins and Foxo1 levels in the retinal vasculature.

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“…Specific pharmacological inhibition and genetic deletion of NF-kB has been shown to attenuate functional and structural injury in mice in pre-clinical models of acute renal ischemia reperfusion injury (51) and in chronic models of chronic kidney disease (33) and diabetic nephropathy (20)(40). NLRP3/ASC knockout mice consistently display protection against renal injury in both the acute and chronic setting including diabetic nephropathy (52) and westerndiet induced diabetic nephropathy (53).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Bruton’s tyrosine kinase reduces NF-kB and NLRP3 inflammasome activity preventing insulin resistance and microvascular disease

Purvis

Collino

Tavio

et al. 2019

Preprint

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Activation of inflammatory pathways in myeloid cells initiates insulin resistance leading to the development of type-2 diabetes and microvascular disease. Currently, there are no therapies available that target inflammation in T2D or microvascular disease. In the present study we investigate if Bruton's tyrosine kinase (BTK) may represent a novel therapeutic target using the FDA approved medication ibrutinib. Ibrutinib treatment protected high fat diet (HFD)-fed mice from developing insulin resistance and improved glycaemic control by restoring signalling through IRS-1/Akt/GSK-3b pathway. These improvements were independent of body weight and calorific intake. Treatment with ibrutinib to mice fed a HFD reduced NF-κB and reduced inflammatory gene expression, this was coupled with decreased activation of the NLRP3 inflammasome in the diabetic liver and kidney. Ibrutinib treatment also protected mice from the development of diabetic nephropathy by reducing monocyte/macrophage infiltration due to reduced expression of the proinflammatory chemokines. Ibrutinib treatment to human monocyte derived macrophages significantly reduced pro-inflammatory gene expression and a significant reduction in IL-1b and TNFa after LPS stimulation. In the present study we provide 'proof of concept' evidence that BTK is a novel therapeutic target for the treatment of T2D and ibrutinib may be a candidate for drug repurposing in T2D. inhibition or genetic deletion of components of the NF-kB pathway i) prevent the development of high fat diet induced insulin resistance (20)(21) and ii) slows the progression of microvascular disease. It has a been demonstrated that myeloid specific deletion of IKK-b, but not deletion in hepatocytes or adipocytes that contributes to the development of insulin resistance (18). Currently there are no medicines available for diabetes that target inflammation and/or prevent the development of microvascular complications. Repurposing existing FDA approved medications that have potent anti-inflammatory effects for new indications could be a cost-effective approach to prevent and/or treat the development of microvascular complications of diabetes. Antiinflammatory agents have been shown to be powerful tools in pre-clinical models. However, to date little translational research as followed up on these successes.Bruton's tyrosine kinase (BTK) is a tyrosine kinase that plays an essential role in B lymphocyte development. Mutations in the BTK gene are implicated in the primary immunodeficiency disease X-linked agammaglobulinemia. As well as, being highly expressed in B-lymphocytes, BTK is also highly expressed in monocytes/macrophages (22), the latter is the key cell types that drives the development of insulin resistance. Importantly, BTK is not expressed in hepatocytes or adipocytes the main cell types effected by obesity induced insulin resistance (23). In monocyte/macrophages BTK has a proposed role in signal transduction downstream of numerous TLR's. XID mice, which have non-signaling kinase domain in BTK, have redu...

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Targeting the NLRP3 inflammasome to Reduce Diet-induced Metabolic Abnormalities in Mice

Cited by 58 publications

References 47 publications

Pharmacological Inhibition of NLRP3 Inflammasome Attenuates Myocardial Ischemia/Reperfusion Injury by Activation of RISK and Mitochondrial Pathways

Pharmacological Inhibition of NLRP3 Inflammasome Attenuates Myocardial Ischemia/Reperfusion Injury by Activation of RISK and Mitochondrial Pathways

miR15a regulates NLRP3 inflammasome proteins in the retinal vasculature

Inhibition of Bruton’s tyrosine kinase reduces NF-kB and NLRP3 inflammasome activity preventing insulin resistance and microvascular disease

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