The balance between AIM2-associated inflammation and autophagy: the role of CHMP2A in brain injury after cardiac arrest

Abstract Background Activation of the absent in melanoma 2 (AIM2) inflammasome and impaired autophagosome clearance in neurons contribute significantly to cardiac arrest and return of spontaneous circulation (CA-ROSC) injury, while the mechanism by which the AIM2 inflammasome is regulated and relati...

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Autores principales:	Rongjiao Shao, Xintao Wang, Tianhua Xu, Yiyang Xia, Derong Cui
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	CHMP2A AIM2 inflammasome Autophagy Inflammation Cardiac arrest Brain damage Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/26fbcb5679884ce9be37a13def6f99a4
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spelling	oai:doaj.org-article:26fbcb5679884ce9be37a13def6f99a42021-11-08T11:14:19ZThe balance between AIM2-associated inflammation and autophagy: the role of CHMP2A in brain injury after cardiac arrest10.1186/s12974-021-02307-81742-2094https://doaj.org/article/26fbcb5679884ce9be37a13def6f99a42021-11-01T00:00:00Zhttps://doi.org/10.1186/s12974-021-02307-8https://doaj.org/toc/1742-2094Abstract Background Activation of the absent in melanoma 2 (AIM2) inflammasome and impaired autophagosome clearance in neurons contribute significantly to cardiac arrest and return of spontaneous circulation (CA-ROSC) injury, while the mechanism by which the AIM2 inflammasome is regulated and relationship between the processes remain poorly understood. Recently, charged multivesicular body protein 2A (CHMP2A), a subunit of endosomal sorting complex required for transport (ESCRT), was shown to regulate phagophore closure, and its depletion led to the accumulation of autophagosomes and induced cell death. Here, we investigated whether CHMP2A-mediated autophagy was an underlying mechanism of AIM2-associated inflammation after CA-ROSC and explored the potential link between the AIM2 inflammasome and autophagy under ischemic conditions. Methods AIM2 inflammasome activation and autophagic flux in the cortex were assessed in the CA-ROSC rat model. We injected LV-Vector or LV-CHMP2A virus into the motor cortex with stereotaxic coordinates and divided the rats into four groups: Sham, CA, CA+LV-Vector, and CA+LV-CHMP2A. Neurologic deficit scores (NDSs), balance beam tests, histopathological injury of the brain, and expression of the AIM2 inflammasome and proinflammatory cytokines were analyzed. Results AIM2 inflammasome activation and increased interleukin 1 beta (IL-1β) and IL-18 release were concurrent with reduced levels of CHMP2A-induced autophagy in CA-ROSC rat neurons. In addition, silencing CHMP2A resulted in autophagosome accumulation and decreased autophagic degradation of the AIM2 inflammasome. In parallel, a reduction in AIM2 contributed to autophagy activation and mitigated oxygen–glucose deprivation and reperfusion (OGD-Rep)-induced inflammation. Notably, CHMP2A overexpression in the cortex hindered neuroinflammation, protected against ischemic brain damage, and improved neurologic outcomes after CA. Conclusions Our results support a potential link between autophagy and AIM2 signaling, and targeting CHMP2A may provide new insights into neuroinflammation in the early phase during CA-ROSC.Rongjiao ShaoXintao WangTianhua XuYiyang XiaDerong CuiBMCarticleCHMP2AAIM2 inflammasomeAutophagyInflammationCardiac arrestBrain damageNeurology. Diseases of the nervous systemRC346-429ENJournal of Neuroinflammation, Vol 18, Iss 1, Pp 1-20 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	CHMP2A AIM2 inflammasome Autophagy Inflammation Cardiac arrest Brain damage Neurology. Diseases of the nervous system RC346-429
spellingShingle	CHMP2A AIM2 inflammasome Autophagy Inflammation Cardiac arrest Brain damage Neurology. Diseases of the nervous system RC346-429 Rongjiao Shao Xintao Wang Tianhua Xu Yiyang Xia Derong Cui The balance between AIM2-associated inflammation and autophagy: the role of CHMP2A in brain injury after cardiac arrest
description	Abstract Background Activation of the absent in melanoma 2 (AIM2) inflammasome and impaired autophagosome clearance in neurons contribute significantly to cardiac arrest and return of spontaneous circulation (CA-ROSC) injury, while the mechanism by which the AIM2 inflammasome is regulated and relationship between the processes remain poorly understood. Recently, charged multivesicular body protein 2A (CHMP2A), a subunit of endosomal sorting complex required for transport (ESCRT), was shown to regulate phagophore closure, and its depletion led to the accumulation of autophagosomes and induced cell death. Here, we investigated whether CHMP2A-mediated autophagy was an underlying mechanism of AIM2-associated inflammation after CA-ROSC and explored the potential link between the AIM2 inflammasome and autophagy under ischemic conditions. Methods AIM2 inflammasome activation and autophagic flux in the cortex were assessed in the CA-ROSC rat model. We injected LV-Vector or LV-CHMP2A virus into the motor cortex with stereotaxic coordinates and divided the rats into four groups: Sham, CA, CA+LV-Vector, and CA+LV-CHMP2A. Neurologic deficit scores (NDSs), balance beam tests, histopathological injury of the brain, and expression of the AIM2 inflammasome and proinflammatory cytokines were analyzed. Results AIM2 inflammasome activation and increased interleukin 1 beta (IL-1β) and IL-18 release were concurrent with reduced levels of CHMP2A-induced autophagy in CA-ROSC rat neurons. In addition, silencing CHMP2A resulted in autophagosome accumulation and decreased autophagic degradation of the AIM2 inflammasome. In parallel, a reduction in AIM2 contributed to autophagy activation and mitigated oxygen–glucose deprivation and reperfusion (OGD-Rep)-induced inflammation. Notably, CHMP2A overexpression in the cortex hindered neuroinflammation, protected against ischemic brain damage, and improved neurologic outcomes after CA. Conclusions Our results support a potential link between autophagy and AIM2 signaling, and targeting CHMP2A may provide new insights into neuroinflammation in the early phase during CA-ROSC.
format	article
author	Rongjiao Shao Xintao Wang Tianhua Xu Yiyang Xia Derong Cui
author_facet	Rongjiao Shao Xintao Wang Tianhua Xu Yiyang Xia Derong Cui
author_sort	Rongjiao Shao
title	The balance between AIM2-associated inflammation and autophagy: the role of CHMP2A in brain injury after cardiac arrest
title_short	The balance between AIM2-associated inflammation and autophagy: the role of CHMP2A in brain injury after cardiac arrest
title_full	The balance between AIM2-associated inflammation and autophagy: the role of CHMP2A in brain injury after cardiac arrest
title_fullStr	The balance between AIM2-associated inflammation and autophagy: the role of CHMP2A in brain injury after cardiac arrest
title_full_unstemmed	The balance between AIM2-associated inflammation and autophagy: the role of CHMP2A in brain injury after cardiac arrest
title_sort	balance between aim2-associated inflammation and autophagy: the role of chmp2a in brain injury after cardiac arrest
publisher	BMC
publishDate	2021
url	https://doaj.org/article/26fbcb5679884ce9be37a13def6f99a4
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The balance between AIM2-associated inflammation and autophagy: the role of CHMP2A in brain injury after cardiac arrest

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