IRE1α inhibition attenuates neuronal pyroptosis via miR-125/NLRP1 pathway in a neonatal hypoxic-ischemic encephalopathy rat model
Abstract Background Inhibition of inositol-requiring enzyme-1 alpha (IRE1α), one of the sensor signaling proteins associated with endoplasmic reticulum (ER) stress, has been shown to alleviate brain injury and improve neurological behavior in a neonatal hypoxic-ischemic encephalopathy (HIE) rat mode...
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doaj-cfc07738a13542d88036f0108ded558c2020-11-25T02:04:34ZengBMCJournal of Neuroinflammation1742-20942020-05-0117111510.1186/s12974-020-01796-3IRE1α inhibition attenuates neuronal pyroptosis via miR-125/NLRP1 pathway in a neonatal hypoxic-ischemic encephalopathy rat modelJuan Huang0Weitian Lu1Desislava Met Doycheva2Marcin Gamdzyk3Xiao Hu4Rui Liu5John H. Zhang6Jiping Tang7Institute of Neuroscience, Chongqing Medical UniversityInstitute of Neuroscience, Chongqing Medical UniversityDepartment of Physiology and Pharmacology, Loma Linda UniversityDepartment of Physiology and Pharmacology, Loma Linda UniversityDepartment of Physiology and Pharmacology, Loma Linda UniversityDepartment of Physiology and Pharmacology, Loma Linda UniversityDepartment of Physiology and Pharmacology, Loma Linda UniversityDepartment of Physiology and Pharmacology, Loma Linda UniversityAbstract Background Inhibition of inositol-requiring enzyme-1 alpha (IRE1α), one of the sensor signaling proteins associated with endoplasmic reticulum (ER) stress, has been shown to alleviate brain injury and improve neurological behavior in a neonatal hypoxic-ischemic encephalopathy (HIE) rat model. However, there is no information about the role of IRE1α inhibitor as well as its molecular mechanisms in preventing neuronal pyroptosis induced by NLRP1 (NOD-, LRR- and pyrin domain-containing 1) inflammasome. In the present study, we hypothesized that IRE1α can degrade microRNA-125-b-2-3p (miR-125-b-2-3p) and activate NLRP1/caspased-1 pathway, and subsequently promote neuronal pyroptosis in HIE rat model. Methods Ten-day old unsexed rat pups were subjected to hypoxia-ischemia (HI) injury, and the inhibitor of IRE1α, STF083010, was administered intranasally at 1 h after HI induction. AntimiR-125 or NLRP1 activation CRISPR was administered by intracerebroventricular (i.c.v) injection at 24 h before HI induction. Immunofluorescence staining, western blot analysis, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), brain infarct volume measurement, neurological function tests, and Fluoro-Jade C staining were performed. Results Endogenous phosphorylated IRE1α (p-IRE1α), NLRP1, cleaved caspase-1, interleukin-1β (IL-1β), and interleukin-18 (IL-18) were increased and miR-125-b-2-3p was decreased in HIE rat model. STF083010 administration significantly upregulated the expression of miR-125-b-2-3p, reduced the infarct volume, improved neurobehavioral outcomes and downregulated the protein expression of NLRP1, cleaved caspase-1, IL-1β and IL-18. The protective effects of STF083010 were reversed by antimiR-125 or NLRP1 activation CRISPR. Conclusions IRE1α inhibitor, STF083010, reduced neuronal pyroptosis at least in part via miR-125/NLRP1/caspase-1 signaling pathway after HI. Graphical Abstracthttp://link.springer.com/article/10.1186/s12974-020-01796-3Hypoxic-ischemic encephalopathyIRE1αmiR-125NLPR1InflammasomePyroptosis |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Juan Huang Weitian Lu Desislava Met Doycheva Marcin Gamdzyk Xiao Hu Rui Liu John H. Zhang Jiping Tang |
spellingShingle |
Juan Huang Weitian Lu Desislava Met Doycheva Marcin Gamdzyk Xiao Hu Rui Liu John H. Zhang Jiping Tang IRE1α inhibition attenuates neuronal pyroptosis via miR-125/NLRP1 pathway in a neonatal hypoxic-ischemic encephalopathy rat model Journal of Neuroinflammation Hypoxic-ischemic encephalopathy IRE1α miR-125 NLPR1 Inflammasome Pyroptosis |
author_facet |
Juan Huang Weitian Lu Desislava Met Doycheva Marcin Gamdzyk Xiao Hu Rui Liu John H. Zhang Jiping Tang |
author_sort |
Juan Huang |
title |
IRE1α inhibition attenuates neuronal pyroptosis via miR-125/NLRP1 pathway in a neonatal hypoxic-ischemic encephalopathy rat model |
title_short |
IRE1α inhibition attenuates neuronal pyroptosis via miR-125/NLRP1 pathway in a neonatal hypoxic-ischemic encephalopathy rat model |
title_full |
IRE1α inhibition attenuates neuronal pyroptosis via miR-125/NLRP1 pathway in a neonatal hypoxic-ischemic encephalopathy rat model |
title_fullStr |
IRE1α inhibition attenuates neuronal pyroptosis via miR-125/NLRP1 pathway in a neonatal hypoxic-ischemic encephalopathy rat model |
title_full_unstemmed |
IRE1α inhibition attenuates neuronal pyroptosis via miR-125/NLRP1 pathway in a neonatal hypoxic-ischemic encephalopathy rat model |
title_sort |
ire1α inhibition attenuates neuronal pyroptosis via mir-125/nlrp1 pathway in a neonatal hypoxic-ischemic encephalopathy rat model |
publisher |
BMC |
series |
Journal of Neuroinflammation |
issn |
1742-2094 |
publishDate |
2020-05-01 |
description |
Abstract Background Inhibition of inositol-requiring enzyme-1 alpha (IRE1α), one of the sensor signaling proteins associated with endoplasmic reticulum (ER) stress, has been shown to alleviate brain injury and improve neurological behavior in a neonatal hypoxic-ischemic encephalopathy (HIE) rat model. However, there is no information about the role of IRE1α inhibitor as well as its molecular mechanisms in preventing neuronal pyroptosis induced by NLRP1 (NOD-, LRR- and pyrin domain-containing 1) inflammasome. In the present study, we hypothesized that IRE1α can degrade microRNA-125-b-2-3p (miR-125-b-2-3p) and activate NLRP1/caspased-1 pathway, and subsequently promote neuronal pyroptosis in HIE rat model. Methods Ten-day old unsexed rat pups were subjected to hypoxia-ischemia (HI) injury, and the inhibitor of IRE1α, STF083010, was administered intranasally at 1 h after HI induction. AntimiR-125 or NLRP1 activation CRISPR was administered by intracerebroventricular (i.c.v) injection at 24 h before HI induction. Immunofluorescence staining, western blot analysis, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), brain infarct volume measurement, neurological function tests, and Fluoro-Jade C staining were performed. Results Endogenous phosphorylated IRE1α (p-IRE1α), NLRP1, cleaved caspase-1, interleukin-1β (IL-1β), and interleukin-18 (IL-18) were increased and miR-125-b-2-3p was decreased in HIE rat model. STF083010 administration significantly upregulated the expression of miR-125-b-2-3p, reduced the infarct volume, improved neurobehavioral outcomes and downregulated the protein expression of NLRP1, cleaved caspase-1, IL-1β and IL-18. The protective effects of STF083010 were reversed by antimiR-125 or NLRP1 activation CRISPR. Conclusions IRE1α inhibitor, STF083010, reduced neuronal pyroptosis at least in part via miR-125/NLRP1/caspase-1 signaling pathway after HI. Graphical Abstract |
topic |
Hypoxic-ischemic encephalopathy IRE1α miR-125 NLPR1 Inflammasome Pyroptosis |
url |
http://link.springer.com/article/10.1186/s12974-020-01796-3 |
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