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NEK7 Coordinates Rapid Neuroinflammation After Subarachnoid Hemorrhage in Mice

Background: Subarachnoid hemorrhage (SAH) is a devastating disease which leads to high morbidity and mortality. Recent studies have indicated that, never in mitosis gene A-related expressed kinase 7 (NEK7), is involved in NLRP3 (NLR family, pyrin domain containing 3) associated inflammation, which m...

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Autores principales: Li, Gen, Dong, Yushu, Liu, Dongdong, Zou, Zheng, Hao, Guangzhi, Gao, Xu, Pan, Pengyu, Liang, Guobiao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360676/
https://www.ncbi.nlm.nih.gov/pubmed/32733353
http://dx.doi.org/10.3389/fneur.2020.00551
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author Li, Gen
Dong, Yushu
Liu, Dongdong
Zou, Zheng
Hao, Guangzhi
Gao, Xu
Pan, Pengyu
Liang, Guobiao
author_facet Li, Gen
Dong, Yushu
Liu, Dongdong
Zou, Zheng
Hao, Guangzhi
Gao, Xu
Pan, Pengyu
Liang, Guobiao
author_sort Li, Gen
collection PubMed
description Background: Subarachnoid hemorrhage (SAH) is a devastating disease which leads to high morbidity and mortality. Recent studies have indicated that, never in mitosis gene A-related expressed kinase 7 (NEK7), is involved in NLRP3 (NLR family, pyrin domain containing 3) associated inflammation, which may result in subsequent cellular and vascular damage. The aim of this study was to investigate whether NEK7 is involved in the pathophysiology of subarachnoid hemorrhage. Methods: 455 adult male C57B6J mice, weighing 22 to 30 g, were used to investigate the time course of NEK7 expression in the ipsilateral cortex after SAH, and to investigate the intrinsic function and mechanism of NEK7. A vascular puncture model was used to create the mouse SAH model, and intracerebroventricular injection was used to deliver NEK7 recombinant protein, NEK7 small interfering RNA, nigericin, and MCC950. Neurological score, brain water content, Evans blue extravasation, immunofluorescence, and western blot were evaluated for neurological outcome, neuronal apoptosis, blood-brain barrier damage, microglia accumulation, and the mechanism of NEK7 and NLRP3 activation. Results: Our results exhibited that intrinsic NEK7 was elevated after SAH in the cortex of the left/ipsilateral hemisphere and was colocalized with microglia, endothelial cells, neuron, astrocyte, and oligodendrocyte, and highly expressed in microglia and endothelial cells after SAH. NEK7 recombinant protein aggravated neurological deficits, brain edema, neuronal apoptosis, BBB permeability, microglial accumulation, and activated caspase-1 and IL-1β maturation, while NEK7 small interfering RNA injection reversed those effects. Nigericin administration enhanced ASC oligomerization, caspase-1 and IL-1β maturation without increasing the protein level of NLRP3, and ASC oligomerization and caspase-1 IL-1β maturation reduced when combined with NEK7 knockdown or MCC950 delivery. We found the level of NEK7 expression increased after SAH and could activate the downstream NLRP3 pathway to induce caspase-1, IL-1β expression and then increased the BBB opening, microglia accumulation and neuronal apoptosis after SAH. Conclusions: This study demonstrated for the first time that NEK7 mediated the harmful effects of neuronal apoptosis and BBB disruption after SAH, which may potentially be mediated by the NEK7/NLRP3 signal. NEK7 served as a co-component for NLRP3 inflammasome activation after SAH. NEK7 may be a promising target on the management of SAH patients.
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spelling pubmed-73606762020-07-29 NEK7 Coordinates Rapid Neuroinflammation After Subarachnoid Hemorrhage in Mice Li, Gen Dong, Yushu Liu, Dongdong Zou, Zheng Hao, Guangzhi Gao, Xu Pan, Pengyu Liang, Guobiao Front Neurol Neurology Background: Subarachnoid hemorrhage (SAH) is a devastating disease which leads to high morbidity and mortality. Recent studies have indicated that, never in mitosis gene A-related expressed kinase 7 (NEK7), is involved in NLRP3 (NLR family, pyrin domain containing 3) associated inflammation, which may result in subsequent cellular and vascular damage. The aim of this study was to investigate whether NEK7 is involved in the pathophysiology of subarachnoid hemorrhage. Methods: 455 adult male C57B6J mice, weighing 22 to 30 g, were used to investigate the time course of NEK7 expression in the ipsilateral cortex after SAH, and to investigate the intrinsic function and mechanism of NEK7. A vascular puncture model was used to create the mouse SAH model, and intracerebroventricular injection was used to deliver NEK7 recombinant protein, NEK7 small interfering RNA, nigericin, and MCC950. Neurological score, brain water content, Evans blue extravasation, immunofluorescence, and western blot were evaluated for neurological outcome, neuronal apoptosis, blood-brain barrier damage, microglia accumulation, and the mechanism of NEK7 and NLRP3 activation. Results: Our results exhibited that intrinsic NEK7 was elevated after SAH in the cortex of the left/ipsilateral hemisphere and was colocalized with microglia, endothelial cells, neuron, astrocyte, and oligodendrocyte, and highly expressed in microglia and endothelial cells after SAH. NEK7 recombinant protein aggravated neurological deficits, brain edema, neuronal apoptosis, BBB permeability, microglial accumulation, and activated caspase-1 and IL-1β maturation, while NEK7 small interfering RNA injection reversed those effects. Nigericin administration enhanced ASC oligomerization, caspase-1 and IL-1β maturation without increasing the protein level of NLRP3, and ASC oligomerization and caspase-1 IL-1β maturation reduced when combined with NEK7 knockdown or MCC950 delivery. We found the level of NEK7 expression increased after SAH and could activate the downstream NLRP3 pathway to induce caspase-1, IL-1β expression and then increased the BBB opening, microglia accumulation and neuronal apoptosis after SAH. Conclusions: This study demonstrated for the first time that NEK7 mediated the harmful effects of neuronal apoptosis and BBB disruption after SAH, which may potentially be mediated by the NEK7/NLRP3 signal. NEK7 served as a co-component for NLRP3 inflammasome activation after SAH. NEK7 may be a promising target on the management of SAH patients. Frontiers Media S.A. 2020-07-08 /pmc/articles/PMC7360676/ /pubmed/32733353 http://dx.doi.org/10.3389/fneur.2020.00551 Text en Copyright © 2020 Li, Dong, Liu, Zou, Hao, Gao, Pan and Liang. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neurology
Li, Gen
Dong, Yushu
Liu, Dongdong
Zou, Zheng
Hao, Guangzhi
Gao, Xu
Pan, Pengyu
Liang, Guobiao
NEK7 Coordinates Rapid Neuroinflammation After Subarachnoid Hemorrhage in Mice
title NEK7 Coordinates Rapid Neuroinflammation After Subarachnoid Hemorrhage in Mice
title_full NEK7 Coordinates Rapid Neuroinflammation After Subarachnoid Hemorrhage in Mice
title_fullStr NEK7 Coordinates Rapid Neuroinflammation After Subarachnoid Hemorrhage in Mice
title_full_unstemmed NEK7 Coordinates Rapid Neuroinflammation After Subarachnoid Hemorrhage in Mice
title_short NEK7 Coordinates Rapid Neuroinflammation After Subarachnoid Hemorrhage in Mice
title_sort nek7 coordinates rapid neuroinflammation after subarachnoid hemorrhage in mice
topic Neurology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360676/
https://www.ncbi.nlm.nih.gov/pubmed/32733353
http://dx.doi.org/10.3389/fneur.2020.00551
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