Cargando…

Parkin-Dependent Mitophagy Is Required for the Inhibition of ATF4 on NLRP3 Inflammasome Activation in Cerebral Ischemia-Reperfusion Injury in Rats

Background: Nod-like receptor protein 3 (NLRP3) inflammasome is a crucial contributor in the inflammatory process during cerebral ischemia/reperfusion (I/R) injury. ATF4 plays a pivotal role in the pathogenesis of cerebral I/R injury, however, its function and underlying mechanism are not fully char...

Descripción completa

Detalles Bibliográficos
Autores principales: He, Qi, Li, Zhenyu, Meng, Changchang, Wu, Jingxian, Zhao, Yong, Zhao, Jing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721752/
https://www.ncbi.nlm.nih.gov/pubmed/31416289
http://dx.doi.org/10.3390/cells8080897
_version_ 1783448413340172288
author He, Qi
Li, Zhenyu
Meng, Changchang
Wu, Jingxian
Zhao, Yong
Zhao, Jing
author_facet He, Qi
Li, Zhenyu
Meng, Changchang
Wu, Jingxian
Zhao, Yong
Zhao, Jing
author_sort He, Qi
collection PubMed
description Background: Nod-like receptor protein 3 (NLRP3) inflammasome is a crucial contributor in the inflammatory process during cerebral ischemia/reperfusion (I/R) injury. ATF4 plays a pivotal role in the pathogenesis of cerebral I/R injury, however, its function and underlying mechanism are not fully characterized yet. In the current study, we examined whether ATF4 ameliorates cerebral I/R injury by inhibiting NLRP3 inflammasome activation and whether mitophagy is involved in this process. In addition, we explored the role of parkin in ATF4-mediated protective effects. Method: To address these issues, healthy male adult Sprague-Dawley rats were exposed to middle cerebral artery occlusion for 1 h followed by 24 h reperfusion. Adeno-associated virus (AAV) and siRNA were injected into rats to overexpress and knockdown ATF4 expression, respectively. After pretreatment with AAV, mdivi-1(mitochondrial division inhibitor-1) was injected into rats to block mitophagy activity. Parkin expression was knockdown using specific siRNA after AAV pretreatment. Result: Data showed that ATF4 overexpression induced by AAV was protective against cerebral I/R injury, as evidenced by reduced cerebral infraction volume, decreased neurological scores and improved outcomes of HE and Nissl staining. In addition, overexpression of ATF4 gene was able to up-regulate Parkin expression, enhance mitophagy activity and inhibit NLRP3 inflammasome-mediated inflammatory response. ATF4 knockdown induced by siRNA resulted in the opposite effects. Furthermore, ATF4-mediated inhibition of NLRP3 inflammasome activation was strongly affected by mitophagy blockage upon mdivi-1 injection. Besides, ATF4-mediated increase of mitophagy activity and inhibition of NLRP3 inflammasome activation were effectively reversed by Parkin knockdown using siRNA. Conclusion: Our study demonstrated that ATF4 is able to alleviate cerebral I/R injury by suppressing NLRP3 inflammasome activation through parkin-dependent mitophagy activity. These results may provide a new strategy to relieve cerebral I/R injury by modulating mitophagy-NLRP3 inflammasome axis.
format Online
Article
Text
id pubmed-6721752
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-67217522019-09-10 Parkin-Dependent Mitophagy Is Required for the Inhibition of ATF4 on NLRP3 Inflammasome Activation in Cerebral Ischemia-Reperfusion Injury in Rats He, Qi Li, Zhenyu Meng, Changchang Wu, Jingxian Zhao, Yong Zhao, Jing Cells Article Background: Nod-like receptor protein 3 (NLRP3) inflammasome is a crucial contributor in the inflammatory process during cerebral ischemia/reperfusion (I/R) injury. ATF4 plays a pivotal role in the pathogenesis of cerebral I/R injury, however, its function and underlying mechanism are not fully characterized yet. In the current study, we examined whether ATF4 ameliorates cerebral I/R injury by inhibiting NLRP3 inflammasome activation and whether mitophagy is involved in this process. In addition, we explored the role of parkin in ATF4-mediated protective effects. Method: To address these issues, healthy male adult Sprague-Dawley rats were exposed to middle cerebral artery occlusion for 1 h followed by 24 h reperfusion. Adeno-associated virus (AAV) and siRNA were injected into rats to overexpress and knockdown ATF4 expression, respectively. After pretreatment with AAV, mdivi-1(mitochondrial division inhibitor-1) was injected into rats to block mitophagy activity. Parkin expression was knockdown using specific siRNA after AAV pretreatment. Result: Data showed that ATF4 overexpression induced by AAV was protective against cerebral I/R injury, as evidenced by reduced cerebral infraction volume, decreased neurological scores and improved outcomes of HE and Nissl staining. In addition, overexpression of ATF4 gene was able to up-regulate Parkin expression, enhance mitophagy activity and inhibit NLRP3 inflammasome-mediated inflammatory response. ATF4 knockdown induced by siRNA resulted in the opposite effects. Furthermore, ATF4-mediated inhibition of NLRP3 inflammasome activation was strongly affected by mitophagy blockage upon mdivi-1 injection. Besides, ATF4-mediated increase of mitophagy activity and inhibition of NLRP3 inflammasome activation were effectively reversed by Parkin knockdown using siRNA. Conclusion: Our study demonstrated that ATF4 is able to alleviate cerebral I/R injury by suppressing NLRP3 inflammasome activation through parkin-dependent mitophagy activity. These results may provide a new strategy to relieve cerebral I/R injury by modulating mitophagy-NLRP3 inflammasome axis. MDPI 2019-08-14 /pmc/articles/PMC6721752/ /pubmed/31416289 http://dx.doi.org/10.3390/cells8080897 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
He, Qi
Li, Zhenyu
Meng, Changchang
Wu, Jingxian
Zhao, Yong
Zhao, Jing
Parkin-Dependent Mitophagy Is Required for the Inhibition of ATF4 on NLRP3 Inflammasome Activation in Cerebral Ischemia-Reperfusion Injury in Rats
title Parkin-Dependent Mitophagy Is Required for the Inhibition of ATF4 on NLRP3 Inflammasome Activation in Cerebral Ischemia-Reperfusion Injury in Rats
title_full Parkin-Dependent Mitophagy Is Required for the Inhibition of ATF4 on NLRP3 Inflammasome Activation in Cerebral Ischemia-Reperfusion Injury in Rats
title_fullStr Parkin-Dependent Mitophagy Is Required for the Inhibition of ATF4 on NLRP3 Inflammasome Activation in Cerebral Ischemia-Reperfusion Injury in Rats
title_full_unstemmed Parkin-Dependent Mitophagy Is Required for the Inhibition of ATF4 on NLRP3 Inflammasome Activation in Cerebral Ischemia-Reperfusion Injury in Rats
title_short Parkin-Dependent Mitophagy Is Required for the Inhibition of ATF4 on NLRP3 Inflammasome Activation in Cerebral Ischemia-Reperfusion Injury in Rats
title_sort parkin-dependent mitophagy is required for the inhibition of atf4 on nlrp3 inflammasome activation in cerebral ischemia-reperfusion injury in rats
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6721752/
https://www.ncbi.nlm.nih.gov/pubmed/31416289
http://dx.doi.org/10.3390/cells8080897
work_keys_str_mv AT heqi parkindependentmitophagyisrequiredfortheinhibitionofatf4onnlrp3inflammasomeactivationincerebralischemiareperfusioninjuryinrats
AT lizhenyu parkindependentmitophagyisrequiredfortheinhibitionofatf4onnlrp3inflammasomeactivationincerebralischemiareperfusioninjuryinrats
AT mengchangchang parkindependentmitophagyisrequiredfortheinhibitionofatf4onnlrp3inflammasomeactivationincerebralischemiareperfusioninjuryinrats
AT wujingxian parkindependentmitophagyisrequiredfortheinhibitionofatf4onnlrp3inflammasomeactivationincerebralischemiareperfusioninjuryinrats
AT zhaoyong parkindependentmitophagyisrequiredfortheinhibitionofatf4onnlrp3inflammasomeactivationincerebralischemiareperfusioninjuryinrats
AT zhaojing parkindependentmitophagyisrequiredfortheinhibitionofatf4onnlrp3inflammasomeactivationincerebralischemiareperfusioninjuryinrats