Nrf2 inhibits NLRP3 inflammasome activation through regulating Trx1/TXNIP complex in cerebral ischemia reperfusion injury

Hou, Yanghao; Wang, Yueting; He, Qi; Li, Lingyu; Xie, Hui; Zhao, Yong; Zhao, Jing

doi:10.1016/j.bbr.2017.06.027

Cited by 231 publications

(158 citation statements)

References 24 publications

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“…The upregulation of SIRT1 activates Nrf2 through the inhibition of p53 or activation of AMPK [59][60][61]. In addition, it is known that in ischemic injury Nrf2 suppresses NLRP3 inflammasome activation through regulating the thioredoxin-interacting protein (TXNIP) complex [62]. Thus, Nrf2 may be linked with negative regulation of the NLRP3 inflammasome by SIRT1; however, further experimental studies are needed to explore this concept.…”

Section: Discussionmentioning

confidence: 99%

SIRT1 Alleviates LPS-Induced IL-1β Production by Suppressing NLRP3 Inflammasome Activation and ROS Production in Trophoblasts

Park

Shin

Bae

et al. 2020

Cells

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Emerging evidence indicates that aberrant maternal inflammation is associated with several pregnancy-related disorders such as preeclampsia, preterm birth, and intrauterine growth restriction. Sirtuin1 (SIRT1), a class III histone deacetylase, is involved in the regulation of various physiopathological processes including cellular inflammation and metabolism. However, the effect of SIRT1 on the placental proinflammatory environment remains to be elucidated. In this study, we investigated the effect of SIRT1 on lipopolysaccharide (LPS)-induced NLRP3 inflammasome activation and its underlying mechanisms in human first-trimester trophoblasts (Sw.71 and HTR-8/SVneo cells). Treatment with LPS elevated SIRT1 expression and induced NLRP3 inflammasome activation in mouse placental tissues and human trophoblasts. Knockdown of SIRT1 enhanced LPS-induced NLRP3 inflammasome activation, inflammatory signaling, and subsequent interleukin (IL)-1β secretion. Furthermore, knockdown of NLRP3 considerably attenuated the increase of IL-1β secretion in SIRT1-knockdown cells treated with LPS. Moreover, SIRT1 inhibited LPS-induced NLRP3 inflammasome activation by reducing oxidative stress. This study revealed a novel mechanism via which SIRT1 exerts anti-inflammatory effects, suggesting that SIRT1 is a potential therapeutic target for the prevention of inflammation-associated pregnancy-related complications.

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Section: Discussionmentioning

confidence: 99%

SIRT1 Alleviates LPS-Induced IL-1β Production by Suppressing NLRP3 Inflammasome Activation and ROS Production in Trophoblasts

Park

Shin

Bae

et al. 2020

Cells

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“…In this study, BV2 cells and PC12 cells were respectively used as microglia and neuron cell models for the investigation of the anti-inflammatory effect of Ala. Interactions between proinflammatory factors are involved in the occurrence, development, and outcome of neuroinflammatory injury [37]. After the cells were cultured with LPS, proinflammatory factors were expressed in the BV2 cells and caused necrosis and apoptosis of the PC12 cells.…”

Section: Discussionmentioning

confidence: 99%

Anti-Neuroinflammatory Effect of Alantolactone through the Suppression of the NF-κB and MAPK Signaling Pathways

Tan

Wang

et al. 2019

Cells

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Neuroinflammation is a major cause of central nervous system (CNS) damage and can result in long-term disability and mortality. Therefore, the development of effective anti-neuroinflammatory agents for neuroprotection is vital. To our surprise, the naturally occurring molecule alantolactone (Ala) was reported to significantly inhibit tumor growth and metastasis as a result of its excellent anti-inflammatory effects. Thus, we proposed that it could also act as an anti-neuroinflammatory agent. Thus, in this study, a coculture system of BV2 cells and PC12 cells were used as an in vitro neuroinflammatory model to investigate the anti-neuroinflammatory mechanism of Ala. The results indicated that Ala downregulated the expression of proinflammatory factors by suppressing the nuclear factor kappa light-chain enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Further evaluation using a middle cerebral artery occlusion and reperfusion (MCAO/R) rat model supported the conclusion that Ala could (1) alleviate cerebral ischemia-reperfusion injury; (2) reduce neurological deficits, cerebral infarct volume, and brain edema; and (3) attenuate the apoptosis and necrosis of neurons. In sum, Ala demonstrates anti-neuroinflammatory properties that contribute to the amelioration of CNS damage, and it could be a promising candidate for future applications in CNS injury treatment.

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“…In this regard, due to its direct interactions with TXN, the role of TXNIP in control of cellular redox balance has been largely studied (3,6). However, it also seems clear that TXNIP has several additional functions not necessarily related to its inhibition of TXN, including activation of the NLRP3 inflammasome (3,(7)(8)(9) and suppression of the activities of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor (10). This is interesting, because Nrf2 also suppresses TXNIP expression (11), which yields a complex web of possible regulation pathways among TXNIP, TXN, Nrf2, and the inflammasome since TXN and Nrf2 are also intimately linked with each other as well as with NLRP3 inflammasome activation (10,12,13).…”

mentioning

confidence: 99%

“…However, it also seems clear that TXNIP has several additional functions not necessarily related to its inhibition of TXN, including activation of the NLRP3 inflammasome (3,(7)(8)(9) and suppression of the activities of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) transcription factor (10). This is interesting, because Nrf2 also suppresses TXNIP expression (11), which yields a complex web of possible regulation pathways among TXNIP, TXN, Nrf2, and the inflammasome since TXN and Nrf2 are also intimately linked with each other as well as with NLRP3 inflammasome activation (10,12,13). It is also noteworthy that Nrf2 activation has major metabolic effects, it channels glucose to anabolic and reductive pathways, and its activation seems to protect from development of diabetes (14,15).…”

mentioning

confidence: 99%

Absence of TXNIP in Humans Leads to Lactic Acidosis and Low Serum Methionine Linked to Deficient Respiration on Pyruvate

et al. 2019

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Thioredoxin-interacting protein (TXNIP) is an α-arrestin that can bind to and inhibit the antioxidant protein thioredoxin (TXN). TXNIP expression is induced by glucose and promotes β-cell apoptosis in the pancreas, and deletion of its gene in mouse models protects against diabetes. TXNIP is currently studied as a potential new target for antidiabetic drug therapy. In this study, we describe a family with a mutation in the TXNIP gene leading to nondetectable expression of TXNIP protein. Symptoms of affected family members include lactic acidosis and low serum methionine levels. Using patient-derived TXNIP-deficient fibroblasts and myoblasts, we show that oxidative phosphorylation is impaired in these cells when given glucose and pyruvate but normalized with malate. Isolated mitochondria from these cells appear to have normal respiratory function. The cells also display a transcriptional pattern suggestive of a high basal activation of the Nrf2 transcription factor. We conclude that a complete lack of TXNIP in human is nonlethal and leads to specific metabolic distortions that are, at least in part, linked to a deficient respiration on pyruvate. The results give important insights into the impact of TXNIP in humans and thus help to further advance the development of antidiabetic drugs targeting this protein.

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Nrf2 inhibits NLRP3 inflammasome activation through regulating Trx1/TXNIP complex in cerebral ischemia reperfusion injury

Cited by 231 publications

References 24 publications

SIRT1 Alleviates LPS-Induced IL-1β Production by Suppressing NLRP3 Inflammasome Activation and ROS Production in Trophoblasts

SIRT1 Alleviates LPS-Induced IL-1β Production by Suppressing NLRP3 Inflammasome Activation and ROS Production in Trophoblasts

Anti-Neuroinflammatory Effect of Alantolactone through the Suppression of the NF-κB and MAPK Signaling Pathways

Absence of TXNIP in Humans Leads to Lactic Acidosis and Low Serum Methionine Linked to Deficient Respiration on Pyruvate

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