Nuclear Factor E2-related Factor-2 (Nrf2) Is Required for NLRP3 and AIM2 Inflammasome Activation

Zhao, Chi; Gillette, Devyn D.; Li, Xinghui; Zhang, Zhibin; Wen, Haitao

doi:10.1074/jbc.m114.563114

Cited by 161 publications

(130 citation statements)

References 52 publications

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“…In this study, we found that Nrf2 activation inhibited NLRP3 inflammasome activation by decreasing ROSinduced NLRP3 transcription. Our in vivo study showed that Nrf2 -/-mice are more susceptible to peritonitis than wild-type mice, which does not agree with a recent study by Zhao et al indicating that Nrf2 -/-mice have significantly less recruitment of immune cells and are less susceptible to peritonitis (51). Aluminduced peritonitis is regarded as a typical NLRP3-IL-1b axis-dependent inflammation animal model, and notably, the dose of alum and its stimulation time influence immune cell recruitment in the peritoneal cavity.…”

Section: Il-1b Was Detected By Elisa (D) Wt Bmdms and Nrf2contrasting

confidence: 51%

Nuclear Factor E2-Related Factor-2 Negatively Regulates NLRP3 Inflammasome Activity by Inhibiting Reactive Oxygen Species-Induced NLRP3 Priming

Liu

Zhang

Ding

et al. 2017

Antioxidants & Redox Signaling

201

140

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Aims: The NLRP3 inflammasome is a multiprotein complex that protects hosts against a variety of pathogens. However, the molecular mechanisms of modulating NLRP3 inflammasome activation, especially at the priming step, are still poorly understood. This study was designed to elucidate the negative regulation of nuclear factor E2-related factor-2 (Nrf2) on the activation of NLRP3 inflammasome. Results: We reported that Nrf2 activation inhibited NLRP3 expression, caspase-1 cleavage, and subsequent IL-1b generation. Compared with normal cells, Nrf2-deficient cells showed upregulated cleaved caspase-1, which were attributed to the increased transcription of NLRP3 caused by excess reactive oxygen species (ROS). Furthermore, priming of the NLRP3 inflammasome was sensitive to the exogenous ROS levels induced by H 2 O 2 or rotenone. Combined with adenosine triphosphate, rotenone triggered higher activity of the NLRP3 inflammasome compared with lipopolysaccharide, suggesting that ROS promoted the priming step. In addition, Nrf2-induced NQO1 was involved in the inhibition of the NLRP3 inflammasome. In an in vivo alum-induced peritonitis mouse model, Nrf2 activation suppressed typical IL-1 signaling-dependent inflammation, whereas Nrf2 -/-mice exhibited a significant increase in the recruitment of immune cell and the generation of IL-1b compared with wild-type mice. Innovation: We elucidated the effects and possible mechanisms of Nrf2 activation-induced NQO1 expression on NLRP3 inflammasome inactivation and established a novel regulatory role of the Nrf2 pathway in ROSinduced NLRP3 priming. Conclusions: We demonstrated Nrf2 negatively regulating NLRP3 inflammasome activity by inhibiting the priming step and suggested that Nrf2 could be a potential target for some uncontrolled inflammasome activation-associated diseases. Antioxid. Redox Signal. 26,[28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43]

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Section: Il-1b Was Detected By Elisa (D) Wt Bmdms and Nrf2contrasting

confidence: 51%

Nuclear Factor E2-Related Factor-2 Negatively Regulates NLRP3 Inflammasome Activity by Inhibiting Reactive Oxygen Species-Induced NLRP3 Priming

Liu

Zhang

Ding

et al. 2017

Antioxidants & Redox Signaling

201

140

View full text Add to dashboard Cite

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“…Considering that Nrf2 modulates CD36 expression in macrophages, Nrf2 may exhibit a pro-atherogenic effect through cholesterol uptake and cholesterol crystal-induced Nlrp3 inflammasome activation. It is also suggested that Nrf2 modulates AIM2 inflammasome activity in addition to the Nlrp3 inflammasome [141].…”

Section: Iron Accumulation Is Observed In Atherosclerotic Lesions Ofmentioning

confidence: 99%

Role of Nrf2 in the pathogenesis of atherosclerosis

Mimura

Itoh

2015

Free Radical Biology and Medicine

127

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“…The antioxidant transcription factor nuclear factor (erythroidderived-2)-like 2 (Nrf2) represses TXNIP expression in response to oxidative stress (11). However, Nrf2, which is activated by oxidative stress in livers of NASH patients (52), and upregulated in livers of male Wistar rats with fructoseinduced steatohepatitis (60), can also activate NLRP3 inflammasome (61). It is currently unknown whether the ROS-TXNIP pathway or the ROS-Nrf2 pathway is responsible for NLRP3 inflammasome activation in hepatocytes in the context of fructose-induced NAFLD.…”

Section: Introductionmentioning

confidence: 99%

Reactive Oxygen Species-Induced TXNIP Drives Fructose-Mediated Hepatic Inflammation and Lipid Accumulation Through NLRP3 Inflammasome Activation

Zhang

Chen

et al. 2015

Antioxidants & Redox Signaling

207

144

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Aims: Increased fructose consumption predisposes the liver to nonalcoholic fatty liver disease (NAFLD), but the mechanisms are elusive. Thioredoxin-interacting protein (TXNIP) links oxidative stress to NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and this signaling axis may be involved in fructose-induced NAFLD. Here, we explore the role of reactive oxygen species (ROS)-induced TXNIP overexpression in fructose-mediated hepatic NLRP3 inflammasome activation, inflammation, and lipid accumulation. Results: Rats were fed a 10% fructose diet for 8 weeks and treated with allopurinol and quercetin during the last 4 weeks. Five millimolars of fructose-exposed hepatocytes (primary rat hepatocytes, rat hepatic parenchymal cells [RHPCs], HLO2, HepG2) were co-incubated with antioxidants or caspase-1 inhibitor or subjected to TXNIP or NLRP3 siRNA interference. Fructose induced NLRP3 inflammasome activation and proinflammatory cytokine secretion, janus-activated kinase 2/signal transducers and activators of transcription 3-mediated inflammatory signaling, and expression alteration of lipid metabolism-related genes in cultured hepatocytes and rat livers. NLRP3 silencing and caspase-1 suppression blocked these effects in primary rat hepatocytes and RHPCs, confirming that inflammasome activation alters hepatocyte lipid metabolism. Hepatocellular ROS and TXNIP were increased in animal and cell models. TXNIP silencing blocked NLRP3 inflammasome activation, inflammation, and lipid metabolism perturbations but not ROS induction in fructoseexposed hepatocytes, whereas antioxidants addition abrogated TXNIP induction and diminished the detrimental effects in fructose-exposed hepatocytes and rat livers. Innovation and Conclusions: This study provides a novel mechanism for fructose-induced NAFLD pathogenesis by which the ROS-TXNIP pathway mediates hepatocellular NLRP3 inflammasome activation, inflammation and lipid accumulation. Antioxidant-based interventions can inhibit the ROS-TXNIP pathway. Antioxid. Redox Signal. 22, 848-870.

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Nuclear Factor E2-related Factor-2 (Nrf2) Is Required for NLRP3 and AIM2 Inflammasome Activation

Cited by 161 publications

References 52 publications

Nuclear Factor E2-Related Factor-2 Negatively Regulates NLRP3 Inflammasome Activity by Inhibiting Reactive Oxygen Species-Induced NLRP3 Priming

Nuclear Factor E2-Related Factor-2 Negatively Regulates NLRP3 Inflammasome Activity by Inhibiting Reactive Oxygen Species-Induced NLRP3 Priming

Role of Nrf2 in the pathogenesis of atherosclerosis

Reactive Oxygen Species-Induced TXNIP Drives Fructose-Mediated Hepatic Inflammation and Lipid Accumulation Through NLRP3 Inflammasome Activation

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