TXNIP-mediated nuclear factor-κB signaling pathway and intracellular shifting of TXNIP in uric acid-induced NLRP3 inflammasome

Kim, Seong-Kyu; Choe, Jung‐Yoon; Park, Ki-Yeon

doi:10.1016/j.bbrc.2019.02.141

Cited by 47 publications

(36 citation statements)

References 22 publications

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“…TXNIP is an important member of the body’s antioxidant stress response thioredoxin, mainly playing an oxidative stress role [24]. Recent studies have found that TXNIP can bind to and activate NLRP3 in a diseased state, thereby activating NLRP3 signaling pathway [22,24]. Our present data showed that Gal-3 regulates TXNIP/NLRP3 signaling pathway to promote neuroinflammation in SCI.…”

Section: Discussionsupporting

confidence: 57%

“…In addition, it also promotes the mature and extracellular secretion of IL-1β to trigger inflammatory responses, thereby exerting a pathogenic effect in multiple systems and organs [23]. TXNIP is an important member of the body’s antioxidant stress response thioredoxin, mainly playing an oxidative stress role [24]. Recent studies have found that TXNIP can bind to and activate NLRP3 in a diseased state, thereby activating NLRP3 signaling pathway [22,24].…”

Section: Discussionmentioning

confidence: 99%

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Gal-3 is a potential biomarker for spinal cord injury and Gal-3 deficiency attenuates neuroinflammation through ROS/TXNIP/NLRP3 signaling pathway

Ren

Sheng

et al. 2019

Bioscience Reports

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Spinal cord injury (SCI) often occurs in young and middle-aged population. The present study aimed to clarify the function of Galectin-3 (Gal-3) in neuroinflammation of SCI. Sprague–Dawley (SD) rat models with SCI were established in vivo. PC12 cell model in vitro was induced by lipopolysaccharide (LPS). Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Gene chip were used to analyze the expression levels of genes in the signaling pathway. Histological assessment, ELISA and Western blotting were conducted to evaluate the effects of Gal-3 upon the SCI model. In the in vivo SD rat model, Gal-3 expression level was up-regulated. The inhibition of Gal-3 attenuated the neuroinflammation in SCI model. The inhibition of Gal-3 could also mitigate the neuroinflammation and reactive oxygen species (ROS) in in vitro model. ROS reduced the effect of Gal-3 on oxidative stress in in vitro model. Down-regulating the content of TXNIP decreased the effect of Gal-3 on neuroinflammation in in vitro model. Suppressing the level of NLRP3 could weaken the effect of Gal-3 on neuroinflammation in in vitro model. Our data highlight that the Gal-3 plays a vital role in regulating the severity of neuroinflammation of SCI by enhancing the activation of ROS/TXNIP/NLRP3 signaling pathway. In addition, inflammasome/IL-1β production probably acts as the therapeutic target in SCI.

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Section: Discussionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Gal-3 is a potential biomarker for spinal cord injury and Gal-3 deficiency attenuates neuroinflammation through ROS/TXNIP/NLRP3 signaling pathway

Ren

Sheng

et al. 2019

Bioscience Reports

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“…TXNIP was originally identified as a negative regulator of thioredoxin 53 , and subsequent studies found that TXNIP contributes to a wide array of processes in several tissues. TXNIP is key regulator of NLRP3 inflammasome activation, which plays an important role in liver fibrosis and hepatocellular carcinoma 54 , and its activation is associated with the NLRP3 inflammasome pathway in human diseases 55 . TXNIP has also emerged as an important glucose sensor that regulates glucose uptake in response to insulin 56 and plays an important role in metabolic stress 57,58 .…”

Section: Discussionmentioning

confidence: 99%

Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to PPARA agonism and fasting

et al. 2020

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Exploring the molecular mechanisms that prevent inflammation during caloric restriction may yield promising therapeutic targets. During fasting, activation of the nuclear receptor peroxisome proliferator-activated receptor α (PPARα) promotes the utilization of lipids as an energy source. Herein, we show that ligand activation of PPARα directly upregulates the long non-coding RNA gene Gm15441 through PPARα binding sites within its promoter. Gm15441 expression suppresses its antisense transcript, encoding thioredoxin interacting protein (TXNIP). This, in turn, decreases TXNIP-stimulated NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, caspase-1 (CASP1) cleavage, and proinflammatory interleukin 1β (IL1B) maturation. Gm15441-null mice were developed and shown to be more susceptible to NLRP3 inflammasome activation and to exhibit elevated CASP1 and IL1B cleavage in response to PPARα agonism and fasting. These findings provide evidence for a mechanism by which PPARα attenuates hepatic inflammasome activation in response to metabolic stress through induction of lncRNA Gm15441.

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“…Notably, TXNIP causes an increase in intracellular reactive oxygen species generation (Hong et al, 2016) that may inhibit hepatocellular carcinoma cell proliferation (Li et al, 2017a). TXNIP is key regulator of NLRP3 inflammasome activation, which plays an important role in liver fibrosis and hepatocellular carcinoma (Ringelhan et al, 2018;Wree et al, 2017), and its activation is associated with the NLRP3 inflammasome pathway in human diseases (Bai et al, 2019;Kim et al, 2019;Li et al, 2019). TXNIP has also emerged as an important glucose sensor that regulates glucose uptake in response to insulin (Waldhart et al, 2017) and plays an important role in metabolic stress (Mandala et al, 2016;Wu et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress

Brocker

Kim

Melia

et al. 2019

Preprint

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Fasting paradigms elicit a wide-range of health benefits including suppressing inflammation.Exploring the molecular mechanisms that prevent inflammation during caloric restriction may yield promising new therapeutic targets. During fasting, activation of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARA) promotes the utilization of lipids as an energy source. Herein, we show that ligand activation of PPARA directly upregulates the long non-coding RNA gene Gm15441 through binding sites within its promoter. Gm15441 expression suppresses its antisense transcript, encoding thioredoxin interacting protein (TXNIP). This, in turn, decreases TXNIP-stimulated NLRP3 inflammasome activation, caspase-1 (CASP1) cleavage, and proinflammatory interleukin 1 beta (IL1B) maturation. Gm15441-null mice were developed and shown to be more susceptible to NLRP3 inflammasome activation and to exhibit elevated CASP1 and IL1B cleavage in response to metabolic and inflammatory stimuli. These findings provide evidence for a novel mechanism by which PPARA attenuates hepatic inflammasome activation in response to metabolic stress through lncRNA Gm15441 induction. 4Txnip expression in vivo. Gm15441 LSL mice were treated with a PPARA agonist or fasted to assess how loss of Gm15441 impacts hepatic inflammasome activation in response to both pharmacological and physiologically-induced metabolic stress. TXNIP protein, caspase-1 (CASP1) levels, and interleukin 1 beta (IL1B) cleavage were elevated in Gm15441 LSL mice and were further increased by PPARA activation, indicating that this lncRNA plays a major role in attenuating inflammasome activation. Thus, hepatic PPARA directly regulates the lncRNA Gm15441, which in turn suppresses Txnip expression, which attenuates NLRP3 inflammasome activation during periods of metabolic stress. These studies revealed a novel regulatory mechanism supporting the beneficial effects of fasting, namely, reduced inflammation. Results LncRNA regulation by PPARA is highly tissue-specificTo assess the regulation of lncRNAs by PPARA, RNA-seq was performed using total liver RNA isolated from Ppara +/+ mice, both with and without dietary exposure to the PPARA agonist WY-14643. A lncRNA discovery pipeline was implemented that identified 15,558 liver-expressed lncRNA genes. Of these, 13,343 were intergenic, 1,966 were antisense, and 249 were intragenic lncRNAs. 44% of the 15,558 liver-expressed lncRNAs are considered novel (Melia and Waxman, 2019). Differential gene expression analysis revealed that a total of 1,735 RefSeq genes and 442 liver-expressed lncRNA genes responded to treatment with WY-14643 at an expression foldchange >2 at FDR<0.05, with 968 RefSeq genes and 245 lncRNA genes upregulated, and 767

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TXNIP-mediated nuclear factor-κB signaling pathway and intracellular shifting of TXNIP in uric acid-induced NLRP3 inflammasome

Cited by 47 publications

References 22 publications

Gal-3 is a potential biomarker for spinal cord injury and Gal-3 deficiency attenuates neuroinflammation through ROS/TXNIP/NLRP3 signaling pathway

Gal-3 is a potential biomarker for spinal cord injury and Gal-3 deficiency attenuates neuroinflammation through ROS/TXNIP/NLRP3 signaling pathway

Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to PPARA agonism and fasting

Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress

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