IRE1α inhibition decreased TXNIP/NLRP3 inflammasome activation through miR-17-5p after neonatal hypoxic–ischemic brain injury in rats
Abstract Background The endoplasmic reticulum (ER) is responsible for the control of correct protein folding and protein function which is crucial for cell survival. However, under pathological conditions, such as hypoxia–ischemia (HI), there is an accumulation of unfolded proteins thereby triggerin...
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2018-02-01
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Series: | Journal of Neuroinflammation |
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Online Access: | http://link.springer.com/article/10.1186/s12974-018-1077-9 |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Di Chen Brandon J. Dixon Desislava M. Doycheva Bo Li Yang Zhang Qin Hu Yue He Zongduo Guo Derek Nowrangi Jerry Flores Valery Filippov John H. Zhang Jiping Tang |
spellingShingle |
Di Chen Brandon J. Dixon Desislava M. Doycheva Bo Li Yang Zhang Qin Hu Yue He Zongduo Guo Derek Nowrangi Jerry Flores Valery Filippov John H. Zhang Jiping Tang IRE1α inhibition decreased TXNIP/NLRP3 inflammasome activation through miR-17-5p after neonatal hypoxic–ischemic brain injury in rats Journal of Neuroinflammation Hypoxia–ischemia IRE1α MicroRNA-17 (miR-17) Neonatal Nod-like receptor protein 3 (NLRP3) Thioredoxin-interacting protein (TXNIP) |
author_facet |
Di Chen Brandon J. Dixon Desislava M. Doycheva Bo Li Yang Zhang Qin Hu Yue He Zongduo Guo Derek Nowrangi Jerry Flores Valery Filippov John H. Zhang Jiping Tang |
author_sort |
Di Chen |
title |
IRE1α inhibition decreased TXNIP/NLRP3 inflammasome activation through miR-17-5p after neonatal hypoxic–ischemic brain injury in rats |
title_short |
IRE1α inhibition decreased TXNIP/NLRP3 inflammasome activation through miR-17-5p after neonatal hypoxic–ischemic brain injury in rats |
title_full |
IRE1α inhibition decreased TXNIP/NLRP3 inflammasome activation through miR-17-5p after neonatal hypoxic–ischemic brain injury in rats |
title_fullStr |
IRE1α inhibition decreased TXNIP/NLRP3 inflammasome activation through miR-17-5p after neonatal hypoxic–ischemic brain injury in rats |
title_full_unstemmed |
IRE1α inhibition decreased TXNIP/NLRP3 inflammasome activation through miR-17-5p after neonatal hypoxic–ischemic brain injury in rats |
title_sort |
ire1α inhibition decreased txnip/nlrp3 inflammasome activation through mir-17-5p after neonatal hypoxic–ischemic brain injury in rats |
publisher |
BMC |
series |
Journal of Neuroinflammation |
issn |
1742-2094 |
publishDate |
2018-02-01 |
description |
Abstract Background The endoplasmic reticulum (ER) is responsible for the control of correct protein folding and protein function which is crucial for cell survival. However, under pathological conditions, such as hypoxia–ischemia (HI), there is an accumulation of unfolded proteins thereby triggering the unfolded protein response (UPR) and causing ER stress which is associated with activation of several stress sensor signaling pathways, one of them being the inositol requiring enzyme-1 alpha (IRE1α) signaling pathway. The UPR is regarded as a potential contributor to neuronal cell death and inflammation after HI. In the present study, we sought to investigate whether microRNA-17 (miR-17), a potential IRE1α ribonuclease (RNase) substrate, arbitrates downregulation of thioredoxin-interacting protein (TXNIP) and consequent NLRP3 inflammasome activation in the immature brain after HI injury and whether inhibition of IRE1α may attenuate inflammation via miR-17/TXNIP regulation. Methods Postnatal day 10 rat pups (n = 287) were subjected to unilateral carotid artery ligation followed by 2.5 h of hypoxia (8% O2). STF-083010, an IRE1α RNase inhibitor, was intranasally delivered at 1 h post-HI or followed by an additional one administration per day for 2 days. MiR-17-5p mimic or anti-miR-17-5p inhibitor was injected intracerebroventricularly at 48 h before HI. Infarct volume and body weight were used to evaluate the short-term effects while brain weight, gross and microscopic brain tissue morphologies, and neurobehavioral tests were conducted for the long-term evaluation. Western blots, immunofluorescence staining, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), and co-immunoprecipitation (Co-IP) were used for mechanism studies. Results Endogenous phosphorylated IRE1α expression was significantly increased after HI. Intranasal administration of STF-083010 alleviated brain injury and improved neurological behavior. MiR-17-5p expression was reduced after HI, and this decrease was attenuated by STF-083010 treatment. MiR-17-5p mimic administration ameliorated TXNIP expression, NLRP3 inflammasome activation, caspase-1 cleavage, and IL-1β production, as well as brain infarct volume. Conversely, anti-miR-17-5p inhibitor reversed IRE1α inhibition-induced decrease in TXNIP expression and inflammasome activation, as well as exacerbated brain injury after HI. Conclusions IRE1a-induced UPR pathway may contribute to inflammatory activation and brain injury following neonatal HI. IRE1a activation, through decay of miR-17-5p, elevated TXNIP expression to activate NLRP3 inflammasome and aggravated brain damage. |
topic |
Hypoxia–ischemia IRE1α MicroRNA-17 (miR-17) Neonatal Nod-like receptor protein 3 (NLRP3) Thioredoxin-interacting protein (TXNIP) |
url |
http://link.springer.com/article/10.1186/s12974-018-1077-9 |
work_keys_str_mv |
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doaj-35cc4eb655054ed0a3bdcded8756876c2020-11-25T01:38:35ZengBMCJournal of Neuroinflammation1742-20942018-02-0115111810.1186/s12974-018-1077-9IRE1α inhibition decreased TXNIP/NLRP3 inflammasome activation through miR-17-5p after neonatal hypoxic–ischemic brain injury in ratsDi Chen0Brandon J. Dixon1Desislava M. Doycheva2Bo Li3Yang Zhang4Qin Hu5Yue He6Zongduo Guo7Derek Nowrangi8Jerry Flores9Valery Filippov10John H. Zhang11Jiping Tang12Cerebrovascular Diseases Laboratory, Institute of Neuroscience, Chongqing Medical UniversityDepartment of Basic Sciences, Loma Linda University School of MedicineDepartment of Basic Sciences, Loma Linda University School of MedicineDepartment of Basic Sciences, Loma Linda University School of MedicineDepartment of Basic Sciences, Loma Linda University School of MedicineDepartment of Basic Sciences, Loma Linda University School of MedicineDepartment of Basic Sciences, Loma Linda University School of MedicineDepartment of Basic Sciences, Loma Linda University School of MedicineDepartment of Basic Sciences, Loma Linda University School of MedicineDepartment of Basic Sciences, Loma Linda University School of MedicineDepartment of Basic Sciences, Loma Linda University School of MedicineDepartment of Basic Sciences, Loma Linda University School of MedicineDepartment of Basic Sciences, Loma Linda University School of MedicineAbstract Background The endoplasmic reticulum (ER) is responsible for the control of correct protein folding and protein function which is crucial for cell survival. However, under pathological conditions, such as hypoxia–ischemia (HI), there is an accumulation of unfolded proteins thereby triggering the unfolded protein response (UPR) and causing ER stress which is associated with activation of several stress sensor signaling pathways, one of them being the inositol requiring enzyme-1 alpha (IRE1α) signaling pathway. The UPR is regarded as a potential contributor to neuronal cell death and inflammation after HI. In the present study, we sought to investigate whether microRNA-17 (miR-17), a potential IRE1α ribonuclease (RNase) substrate, arbitrates downregulation of thioredoxin-interacting protein (TXNIP) and consequent NLRP3 inflammasome activation in the immature brain after HI injury and whether inhibition of IRE1α may attenuate inflammation via miR-17/TXNIP regulation. Methods Postnatal day 10 rat pups (n = 287) were subjected to unilateral carotid artery ligation followed by 2.5 h of hypoxia (8% O2). STF-083010, an IRE1α RNase inhibitor, was intranasally delivered at 1 h post-HI or followed by an additional one administration per day for 2 days. MiR-17-5p mimic or anti-miR-17-5p inhibitor was injected intracerebroventricularly at 48 h before HI. Infarct volume and body weight were used to evaluate the short-term effects while brain weight, gross and microscopic brain tissue morphologies, and neurobehavioral tests were conducted for the long-term evaluation. Western blots, immunofluorescence staining, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), and co-immunoprecipitation (Co-IP) were used for mechanism studies. Results Endogenous phosphorylated IRE1α expression was significantly increased after HI. Intranasal administration of STF-083010 alleviated brain injury and improved neurological behavior. MiR-17-5p expression was reduced after HI, and this decrease was attenuated by STF-083010 treatment. MiR-17-5p mimic administration ameliorated TXNIP expression, NLRP3 inflammasome activation, caspase-1 cleavage, and IL-1β production, as well as brain infarct volume. Conversely, anti-miR-17-5p inhibitor reversed IRE1α inhibition-induced decrease in TXNIP expression and inflammasome activation, as well as exacerbated brain injury after HI. Conclusions IRE1a-induced UPR pathway may contribute to inflammatory activation and brain injury following neonatal HI. IRE1a activation, through decay of miR-17-5p, elevated TXNIP expression to activate NLRP3 inflammasome and aggravated brain damage.http://link.springer.com/article/10.1186/s12974-018-1077-9Hypoxia–ischemiaIRE1αMicroRNA-17 (miR-17)NeonatalNod-like receptor protein 3 (NLRP3)Thioredoxin-interacting protein (TXNIP) |