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Erbin protects against sepsis-associated encephalopathy by attenuating microglia pyroptosis via IRE1α/Xbp1s-Ca(2+) axis

BACKGROUND: Microglia pyroptosis-mediated neuroinflammation is thought to be the crucial pathogenesis of sepsis-associated encephalopathy (SAE). Erbin has been reported to be associated with various inflammatory diseases. However, the role of Erbin in SAE and the relationship between Erbin and micro...

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Autores principales: Jing, Guoqing, Zuo, Jing, Fang, Qing, Yuan, Min, Xia, Yun, Jin, Qiyan, Liu, Yuping, Wang, Yanlin, Zhang, Zongze, Liu, Wanhong, Wu, Xiaojing, Song, Xuemin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9520943/
https://www.ncbi.nlm.nih.gov/pubmed/36171629
http://dx.doi.org/10.1186/s12974-022-02598-5
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author Jing, Guoqing
Zuo, Jing
Fang, Qing
Yuan, Min
Xia, Yun
Jin, Qiyan
Liu, Yuping
Wang, Yanlin
Zhang, Zongze
Liu, Wanhong
Wu, Xiaojing
Song, Xuemin
author_facet Jing, Guoqing
Zuo, Jing
Fang, Qing
Yuan, Min
Xia, Yun
Jin, Qiyan
Liu, Yuping
Wang, Yanlin
Zhang, Zongze
Liu, Wanhong
Wu, Xiaojing
Song, Xuemin
author_sort Jing, Guoqing
collection PubMed
description BACKGROUND: Microglia pyroptosis-mediated neuroinflammation is thought to be the crucial pathogenesis of sepsis-associated encephalopathy (SAE). Erbin has been reported to be associated with various inflammatory diseases. However, the role of Erbin in SAE and the relationship between Erbin and microglia pyroptosis are unknown. In this study, we investigated the promising role and underlying molecular mechanism of Erbin in the regulation of microglia pyroptosis. METHODS: WT and Erbin knockout mice underwent cecum ligation perforation (CLP) to induce SAE. Primary mouse microglia and BV2 cells were treated with LPS/nigericin in vitro. Behavioral tests were performed to evaluate cognitive function. Nissl staining and transmission electron microscopy were used to assess histological and structural lesions. ELISA and qPCR were carried out to detect neuroinflammation. Western blot and immunofluorescence were used to analyze protein expression. Flow cytometry and confocal microscopy were utilized to observe the Ca(2+) changes in the cytoplasm and endoplasmic reticulum (ER). To further explore the underlying mechanism, STF083010 was administered to block the IRE1α/Xbp1s pathway. RESULTS: Erbin deletion resulted in more pronounced neuronal damage and cognitive impairment in mice that underwent CLP. Erbin knockout promoted microglial pyroptosis and inflammatory cytokines secretion in vivo and in vitro, which was mediated by activation of the IRE1α/Xbp1s. Treatment with the selective inhibitor STF083010 significantly inhibited IRE1α/Xbp1s pathway activity, decreased intracytoplasmic Ca(2+), attenuated microglial pyroptosis, reduced pro-inflammatory cytokine secretion, lessened neuronal damage, and improved cognitive function. CONCLUSIONS: In SAE, Erbin inhibits IRE1/Xbp1s pathway activity and reduces the ER Ca(2+) influx to the cytoplasm, reducing microglial pyroptosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02598-5.
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spelling pubmed-95209432022-09-30 Erbin protects against sepsis-associated encephalopathy by attenuating microglia pyroptosis via IRE1α/Xbp1s-Ca(2+) axis Jing, Guoqing Zuo, Jing Fang, Qing Yuan, Min Xia, Yun Jin, Qiyan Liu, Yuping Wang, Yanlin Zhang, Zongze Liu, Wanhong Wu, Xiaojing Song, Xuemin J Neuroinflammation Research BACKGROUND: Microglia pyroptosis-mediated neuroinflammation is thought to be the crucial pathogenesis of sepsis-associated encephalopathy (SAE). Erbin has been reported to be associated with various inflammatory diseases. However, the role of Erbin in SAE and the relationship between Erbin and microglia pyroptosis are unknown. In this study, we investigated the promising role and underlying molecular mechanism of Erbin in the regulation of microglia pyroptosis. METHODS: WT and Erbin knockout mice underwent cecum ligation perforation (CLP) to induce SAE. Primary mouse microglia and BV2 cells were treated with LPS/nigericin in vitro. Behavioral tests were performed to evaluate cognitive function. Nissl staining and transmission electron microscopy were used to assess histological and structural lesions. ELISA and qPCR were carried out to detect neuroinflammation. Western blot and immunofluorescence were used to analyze protein expression. Flow cytometry and confocal microscopy were utilized to observe the Ca(2+) changes in the cytoplasm and endoplasmic reticulum (ER). To further explore the underlying mechanism, STF083010 was administered to block the IRE1α/Xbp1s pathway. RESULTS: Erbin deletion resulted in more pronounced neuronal damage and cognitive impairment in mice that underwent CLP. Erbin knockout promoted microglial pyroptosis and inflammatory cytokines secretion in vivo and in vitro, which was mediated by activation of the IRE1α/Xbp1s. Treatment with the selective inhibitor STF083010 significantly inhibited IRE1α/Xbp1s pathway activity, decreased intracytoplasmic Ca(2+), attenuated microglial pyroptosis, reduced pro-inflammatory cytokine secretion, lessened neuronal damage, and improved cognitive function. CONCLUSIONS: In SAE, Erbin inhibits IRE1/Xbp1s pathway activity and reduces the ER Ca(2+) influx to the cytoplasm, reducing microglial pyroptosis. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12974-022-02598-5. BioMed Central 2022-09-28 /pmc/articles/PMC9520943/ /pubmed/36171629 http://dx.doi.org/10.1186/s12974-022-02598-5 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Jing, Guoqing
Zuo, Jing
Fang, Qing
Yuan, Min
Xia, Yun
Jin, Qiyan
Liu, Yuping
Wang, Yanlin
Zhang, Zongze
Liu, Wanhong
Wu, Xiaojing
Song, Xuemin
Erbin protects against sepsis-associated encephalopathy by attenuating microglia pyroptosis via IRE1α/Xbp1s-Ca(2+) axis
title Erbin protects against sepsis-associated encephalopathy by attenuating microglia pyroptosis via IRE1α/Xbp1s-Ca(2+) axis
title_full Erbin protects against sepsis-associated encephalopathy by attenuating microglia pyroptosis via IRE1α/Xbp1s-Ca(2+) axis
title_fullStr Erbin protects against sepsis-associated encephalopathy by attenuating microglia pyroptosis via IRE1α/Xbp1s-Ca(2+) axis
title_full_unstemmed Erbin protects against sepsis-associated encephalopathy by attenuating microglia pyroptosis via IRE1α/Xbp1s-Ca(2+) axis
title_short Erbin protects against sepsis-associated encephalopathy by attenuating microglia pyroptosis via IRE1α/Xbp1s-Ca(2+) axis
title_sort erbin protects against sepsis-associated encephalopathy by attenuating microglia pyroptosis via ire1α/xbp1s-ca(2+) axis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9520943/
https://www.ncbi.nlm.nih.gov/pubmed/36171629
http://dx.doi.org/10.1186/s12974-022-02598-5
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