Skip to main content
Top
Published in: Inflammation Research 1/2018

01-01-2018 | Original Research Paper

Nrf2/ARE pathway inhibits ROS-induced NLRP3 inflammasome activation in BV2 cells after cerebral ischemia reperfusion

Authors: Xiujian Xu, Liang Zhang, Xinchun Ye, Qi Hao, Tao Zhang, Guiyun Cui, Ming Yu

Published in: Inflammation Research | Issue 1/2018

Login to get access

Abstract

Objective

Current therapies for ischemia/reperfusion are insufficient because of our poor understanding of the mechanisms of brain injury after ischemic stroke. As a vital component of the innate immune system, NLRP3 inflammasome contributes to ischemic brain injury; however, a detailed understanding of their molecular mechanisms is unknown. This study was designed to investigate the effect of nuclear factor E2-related factor-2 (Nrf2) on NLRP3 inflammasome.

Materials and methods

BV2 microglial cells were pretreated with tert-butylhydroquinone or Nrf2 CRISPR plasmid before oxygen–glucose deprivation/reoxygenation (OGDR) exposure. Then we observed the effect of Nrf2 on NLRP3 inflammasome.

Results

We identified that Nrf2 activation inhibited NLRP3 inflammasome expression and subsequent IL-1β generation. Furthermore, the activation of NLRP3 inflammasome was sensitive to the reactive oxygen species (ROS) level and Nrf2 could decrease the production of ROS. Additionally, as a Nrf2-targeted ARE gene, NADPH quinone oxidoreductase 1 was involved in the inhibition of the NLRP3 inflammasome.

Conclusion

We elucidated an inhibitory regulation of Nrf2/ARE pathway on ROS-induced NLRP3 inflammasome activation in BV2 microglial cells after OGDR exposure.
Literature
1.
go back to reference Yang F, Wang Z, Wei X, Han H, Meng X, Zhang Y, et al. NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke. J Cereb Blood Flow Metab. 2014;34:660–7.CrossRefPubMedPubMedCentral Yang F, Wang Z, Wei X, Han H, Meng X, Zhang Y, et al. NLRP3 deficiency ameliorates neurovascular damage in experimental ischemic stroke. J Cereb Blood Flow Metab. 2014;34:660–7.CrossRefPubMedPubMedCentral
2.
go back to reference Gao L, Dong Q, Song Z, Shen F, Shi J, Li Y. NLRP3 inflammasome: a promising target in ischemic stroke. Inflamm Res. 2017;66:17–24.CrossRefPubMed Gao L, Dong Q, Song Z, Shen F, Shi J, Li Y. NLRP3 inflammasome: a promising target in ischemic stroke. Inflamm Res. 2017;66:17–24.CrossRefPubMed
3.
go back to reference Lamkanfi M, Dixit VM. Inflammasomes and their roles in health and disease. Annu Rev Cell Dev Biol. 2012;28:137–61.CrossRefPubMed Lamkanfi M, Dixit VM. Inflammasomes and their roles in health and disease. Annu Rev Cell Dev Biol. 2012;28:137–61.CrossRefPubMed
4.
go back to reference Prochnicki T, Mangan MS, Latz E. Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation. F1000Res. 2016;5:1469.CrossRef Prochnicki T, Mangan MS, Latz E. Recent insights into the molecular mechanisms of the NLRP3 inflammasome activation. F1000Res. 2016;5:1469.CrossRef
6.
go back to reference Jankovic D, Ganesan J, Bscheider M, Stickel N, Weber FC, Guarda G, et al. The Nlrp3 inflammasome regulates acute graft-versus-host disease. J Exp Med. 2013;210:1899–910.CrossRefPubMedPubMedCentral Jankovic D, Ganesan J, Bscheider M, Stickel N, Weber FC, Guarda G, et al. The Nlrp3 inflammasome regulates acute graft-versus-host disease. J Exp Med. 2013;210:1899–910.CrossRefPubMedPubMedCentral
7.
go back to reference Saresella M, La Rosa F, Piancone F, Zoppis M, Marventano I, Calabrese E, et al. The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease. Mol Neurodegeneration. 2016;11:23.CrossRef Saresella M, La Rosa F, Piancone F, Zoppis M, Marventano I, Calabrese E, et al. The NLRP3 and NLRP1 inflammasomes are activated in Alzheimer’s disease. Mol Neurodegeneration. 2016;11:23.CrossRef
8.
go back to reference Ystgaard MB, Sejersted Y, Loberg EM, Lien E, Yndestad A, Saugstad OD. Early upregulation of NLRP3 in the brain of neonatal mice exposed to hypoxia-ischemia: no early neuroprotective effects of NLRP3 deficiency. Neonatology. 2015;108:211–9.CrossRefPubMed Ystgaard MB, Sejersted Y, Loberg EM, Lien E, Yndestad A, Saugstad OD. Early upregulation of NLRP3 in the brain of neonatal mice exposed to hypoxia-ischemia: no early neuroprotective effects of NLRP3 deficiency. Neonatology. 2015;108:211–9.CrossRefPubMed
9.
go back to reference Huai W, Zhao R, Song H, Zhao J, Zhang L, Gao C, et al. Aryl hydrocarbon receptor negatively regulates NLRP3 inflammasome activity by inhibiting NLRP3 transcription. Nat Commun. 2014;5:4738.CrossRefPubMed Huai W, Zhao R, Song H, Zhao J, Zhang L, Gao C, et al. Aryl hydrocarbon receptor negatively regulates NLRP3 inflammasome activity by inhibiting NLRP3 transcription. Nat Commun. 2014;5:4738.CrossRefPubMed
10.
go back to reference Satoh T, Kambe N, Matsue H. NLRP3 activation induces ASC-dependent programmed necrotic cell death, which leads to neutrophilic inflammation. Cell Death Dis. 2013;4:e644.CrossRefPubMedPubMedCentral Satoh T, Kambe N, Matsue H. NLRP3 activation induces ASC-dependent programmed necrotic cell death, which leads to neutrophilic inflammation. Cell Death Dis. 2013;4:e644.CrossRefPubMedPubMedCentral
11.
go back to reference Rubartelli A. Redox control of NLRP3 inflammasome activation in health and disease. J Leukoc Biol. 2012;92:951–8.CrossRefPubMed Rubartelli A. Redox control of NLRP3 inflammasome activation in health and disease. J Leukoc Biol. 2012;92:951–8.CrossRefPubMed
12.
go back to reference Minutoli L, Puzzolo D, Rinaldi M, Irrera N, Marini H, Arcoraci V, et al. ROS-mediated NLRP3 inflammasome activation in brain, heart, kidney, and testis ischemia/reperfusion injury. Oxidative Med Cell Longev. 2016;2016:2183026.CrossRef Minutoli L, Puzzolo D, Rinaldi M, Irrera N, Marini H, Arcoraci V, et al. ROS-mediated NLRP3 inflammasome activation in brain, heart, kidney, and testis ischemia/reperfusion injury. Oxidative Med Cell Longev. 2016;2016:2183026.CrossRef
13.
go back to reference Suzuki T, Motohashi H, Yamamoto M. Toward clinical application of the Keap1-Nrf2 pathway. Trends Pharmacol Sci. 2013;34:340–6.CrossRefPubMed Suzuki T, Motohashi H, Yamamoto M. Toward clinical application of the Keap1-Nrf2 pathway. Trends Pharmacol Sci. 2013;34:340–6.CrossRefPubMed
15.
go back to reference Zhao H, Eguchi S, Alam A, Ma D. The role of nuclear factor-erythroid 2 related factor 2 (Nrf-2) in the protection against lung injury. Am J Physiol Lung Cell Mol Physiol. 2017;312:L155–62.CrossRefPubMed Zhao H, Eguchi S, Alam A, Ma D. The role of nuclear factor-erythroid 2 related factor 2 (Nrf-2) in the protection against lung injury. Am J Physiol Lung Cell Mol Physiol. 2017;312:L155–62.CrossRefPubMed
16.
go back to reference Turley AE, Zagorski JW, Rockwell CE. The Nrf2 activator tBHQ inhibits T cell activation of primary human CD4 T cells. Cytokine. 2015;71:289–95.CrossRefPubMed Turley AE, Zagorski JW, Rockwell CE. The Nrf2 activator tBHQ inhibits T cell activation of primary human CD4 T cells. Cytokine. 2015;71:289–95.CrossRefPubMed
17.
go back to reference Li W, Khor TO, Xu C, Shen G, Jeong WS, Yu S, et al. Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis. Biochem Pharmacol. 2008;76:1485–9.CrossRefPubMedPubMedCentral Li W, Khor TO, Xu C, Shen G, Jeong WS, Yu S, et al. Activation of Nrf2-antioxidant signaling attenuates NFkappaB-inflammatory response and elicits apoptosis. Biochem Pharmacol. 2008;76:1485–9.CrossRefPubMedPubMedCentral
18.
go back to reference Kovac S, Angelova PR, Holmstrom KM, Zhang Y, Dinkova-Kostova AT, Abramov AY. Nrf2 regulates ROS production by mitochondria and NADPH oxidase. Biochem Biophys Acta. 2015;1850:794–801.CrossRefPubMedPubMedCentral Kovac S, Angelova PR, Holmstrom KM, Zhang Y, Dinkova-Kostova AT, Abramov AY. Nrf2 regulates ROS production by mitochondria and NADPH oxidase. Biochem Biophys Acta. 2015;1850:794–801.CrossRefPubMedPubMedCentral
19.
go back to reference Thimmulappa RK, Lee H, Rangasamy T, Reddy SP, Yamamoto M, Kensler TW, et al. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Investig. 2006;116:984–95.CrossRefPubMedPubMedCentral Thimmulappa RK, Lee H, Rangasamy T, Reddy SP, Yamamoto M, Kensler TW, et al. Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis. J Clin Investig. 2006;116:984–95.CrossRefPubMedPubMedCentral
20.
go back to reference Lambertucci F, Motino O, Villar S, Rigalli JP, de Lujan Alvarez M, Catania VA, et al. Benznidazole, the trypanocidal drug used for Chagas disease, induces hepatic NRF2 activation and attenuates the inflammatory response in a murine model of sepsis. Toxicol Appl Pharmacol. 2017;315:12–22.CrossRefPubMed Lambertucci F, Motino O, Villar S, Rigalli JP, de Lujan Alvarez M, Catania VA, et al. Benznidazole, the trypanocidal drug used for Chagas disease, induces hepatic NRF2 activation and attenuates the inflammatory response in a murine model of sepsis. Toxicol Appl Pharmacol. 2017;315:12–22.CrossRefPubMed
21.
go back to reference Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, et al. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med. 2005;202:47–59.CrossRefPubMedPubMedCentral Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, Fryer AD, et al. Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med. 2005;202:47–59.CrossRefPubMedPubMedCentral
22.
go back to reference Cai M, Yu Z, Wang L, Song X, Zhang J, Zhang Z, et al. Tongxinluo reduces brain edema and inhibits post-ischemic inflammation after middle cerebral artery occlusion in rats. J Ethnopharmacol. 2016;181:136–45.CrossRefPubMed Cai M, Yu Z, Wang L, Song X, Zhang J, Zhang Z, et al. Tongxinluo reduces brain edema and inhibits post-ischemic inflammation after middle cerebral artery occlusion in rats. J Ethnopharmacol. 2016;181:136–45.CrossRefPubMed
23.
go back to reference Juliana C, Fernandes-Alnemri T, Kang S, Farias A, Qin F, Alnemri ES. Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J Biol Chem. 2012;287:36617–22.CrossRefPubMedPubMedCentral Juliana C, Fernandes-Alnemri T, Kang S, Farias A, Qin F, Alnemri ES. Non-transcriptional priming and deubiquitination regulate NLRP3 inflammasome activation. J Biol Chem. 2012;287:36617–22.CrossRefPubMedPubMedCentral
24.
go back to reference Qiu J, Wang M, Zhang J, Cai Q, Lu D, Li Y, et al. The neuroprotection of Sinomenine against ischemic stroke in mice by suppressing NLRP3 inflammasome via AMPK signaling. Int Immunopharmacol. 2016;40:492–500.CrossRefPubMed Qiu J, Wang M, Zhang J, Cai Q, Lu D, Li Y, et al. The neuroprotection of Sinomenine against ischemic stroke in mice by suppressing NLRP3 inflammasome via AMPK signaling. Int Immunopharmacol. 2016;40:492–500.CrossRefPubMed
25.
go back to reference Fann DY, Lee SY, Manzanero S, Tang SC, Gelderblom M, Chunduri P, et al. Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis. 2013;4:e790.CrossRefPubMed Fann DY, Lee SY, Manzanero S, Tang SC, Gelderblom M, Chunduri P, et al. Intravenous immunoglobulin suppresses NLRP1 and NLRP3 inflammasome-mediated neuronal death in ischemic stroke. Cell Death Dis. 2013;4:e790.CrossRefPubMed
26.
go back to reference Yang YX, Zheng LT, Shi JJ, Gao B, Chen YK, Yang HC, et al. Synthesis of 5alpha-cholestan-6-one derivatives and their inhibitory activities of NO production in activated microglia: discovery of a novel neuroinflammation inhibitor. Bioorg Med Chem Lett. 2014;24:1222–7.CrossRefPubMed Yang YX, Zheng LT, Shi JJ, Gao B, Chen YK, Yang HC, et al. Synthesis of 5alpha-cholestan-6-one derivatives and their inhibitory activities of NO production in activated microglia: discovery of a novel neuroinflammation inhibitor. Bioorg Med Chem Lett. 2014;24:1222–7.CrossRefPubMed
27.
go back to reference Ka SM, Lin JC, Lin TJ, Liu FC, Chao LK, Ho CL, et al. Citral alleviates an accelerated and severe lupus nephritis model by inhibiting the activation signal of NLRP3 inflammasome and enhancing Nrf2 activation. Arthritis Res Therapy. 2015;17:331.CrossRef Ka SM, Lin JC, Lin TJ, Liu FC, Chao LK, Ho CL, et al. Citral alleviates an accelerated and severe lupus nephritis model by inhibiting the activation signal of NLRP3 inflammasome and enhancing Nrf2 activation. Arthritis Res Therapy. 2015;17:331.CrossRef
28.
go back to reference Pan CW, Pan ZZ, Hu JJ, Chen WL, Zhou GY, Lin W, et al. Mangiferin alleviates lipopolysaccharide and d-galactosamine-induced acute liver injury by activating the Nrf2 pathway and inhibiting NLRP3 inflammasome activation. Eur J Pharmacol. 2016;770:85–91.CrossRefPubMed Pan CW, Pan ZZ, Hu JJ, Chen WL, Zhou GY, Lin W, et al. Mangiferin alleviates lipopolysaccharide and d-galactosamine-induced acute liver injury by activating the Nrf2 pathway and inhibiting NLRP3 inflammasome activation. Eur J Pharmacol. 2016;770:85–91.CrossRefPubMed
29.
go back to reference Wang Y, Wang H, Qian C, Tang J, Zhou W, Liu X, et al. 3-(2-Oxo-2-phenylethylidene)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(1 1bH)-one (compound 1), a novel potent Nrf2/ARE inducer, protects against DSS-induced colitis via inhibiting NLRP3 inflammasome. Biochem Pharmacol. 2016;101:71–86.CrossRefPubMed Wang Y, Wang H, Qian C, Tang J, Zhou W, Liu X, et al. 3-(2-Oxo-2-phenylethylidene)-2,3,6,7-tetrahydro-1H-pyrazino[2,1-a]isoquinolin-4(1 1bH)-one (compound 1), a novel potent Nrf2/ARE inducer, protects against DSS-induced colitis via inhibiting NLRP3 inflammasome. Biochem Pharmacol. 2016;101:71–86.CrossRefPubMed
30.
go back to reference Tsai PY, Ka SM, Chang JM, Chen HC, Shui HA, Li CY, Hua KF, Chang WL, Huang JJ, Yang SS, Chen A. Epigallocatechin-3-gallate prevents lupus nephritis development in mice via enhancing the Nrf2 antioxidant pathway and inhibiting NLRP3 inflammasome activation. Free Radic Biol Med. 2011;51:744–54.CrossRefPubMed Tsai PY, Ka SM, Chang JM, Chen HC, Shui HA, Li CY, Hua KF, Chang WL, Huang JJ, Yang SS, Chen A. Epigallocatechin-3-gallate prevents lupus nephritis development in mice via enhancing the Nrf2 antioxidant pathway and inhibiting NLRP3 inflammasome activation. Free Radic Biol Med. 2011;51:744–54.CrossRefPubMed
31.
go back to reference Yang SM, Ka SM, Hua KF, Wu TH, Chuang YP, Lin YW, et al. Antroquinonol mitigates an accelerated and progressive IgA nephropathy model in mice by activating the Nrf2 pathway and inhibiting T cells and NLRP3 inflammasome. Free Radic Biol Med. 2013;61:285–97.CrossRefPubMed Yang SM, Ka SM, Hua KF, Wu TH, Chuang YP, Lin YW, et al. Antroquinonol mitigates an accelerated and progressive IgA nephropathy model in mice by activating the Nrf2 pathway and inhibiting T cells and NLRP3 inflammasome. Free Radic Biol Med. 2013;61:285–97.CrossRefPubMed
32.
go back to reference Dong Q, Hou H, Wu J, Chen Y. The Nrf2-ARE pathway is associated with schisandrin b attenuating benzo(a)pyrene-Induced HTR cells damages in vitro. Environ Toxicol. 2016;31:1439–49.CrossRefPubMed Dong Q, Hou H, Wu J, Chen Y. The Nrf2-ARE pathway is associated with schisandrin b attenuating benzo(a)pyrene-Induced HTR cells damages in vitro. Environ Toxicol. 2016;31:1439–49.CrossRefPubMed
33.
go back to reference Duan X, Li J, Li W, Xing X, Zhang Y, Zhao L, et al. Antioxidant tert-butylhydroquinone ameliorates arsenic-induced intracellular damages and apoptosis through induction of Nrf2-dependent antioxidant responses as well as stabilization of anti-apoptotic factor Bcl-2 in human keratinocytes. Free Radic Biol Med. 2016;94:74–87.CrossRefPubMed Duan X, Li J, Li W, Xing X, Zhang Y, Zhao L, et al. Antioxidant tert-butylhydroquinone ameliorates arsenic-induced intracellular damages and apoptosis through induction of Nrf2-dependent antioxidant responses as well as stabilization of anti-apoptotic factor Bcl-2 in human keratinocytes. Free Radic Biol Med. 2016;94:74–87.CrossRefPubMed
35.
go back to reference Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36:401–14.CrossRefPubMedPubMedCentral Shimada K, Crother TR, Karlin J, Dagvadorj J, Chiba N, Chen S, et al. Oxidized mitochondrial DNA activates the NLRP3 inflammasome during apoptosis. Immunity. 2012;36:401–14.CrossRefPubMedPubMedCentral
36.
go back to reference Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21:263–9.PubMedPubMedCentral Youm YH, Nguyen KY, Grant RW, Goldberg EL, Bodogai M, Kim D, et al. The ketone metabolite beta-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease. Nat Med. 2015;21:263–9.PubMedPubMedCentral
Metadata
Title
Nrf2/ARE pathway inhibits ROS-induced NLRP3 inflammasome activation in BV2 cells after cerebral ischemia reperfusion
Authors
Xiujian Xu
Liang Zhang
Xinchun Ye
Qi Hao
Tao Zhang
Guiyun Cui
Ming Yu
Publication date
01-01-2018
Publisher
Springer International Publishing
Published in
Inflammation Research / Issue 1/2018
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI
https://doi.org/10.1007/s00011-017-1095-6

Other articles of this Issue 1/2018

Inflammation Research 1/2018 Go to the issue