Upregulation of Neuronal Cylindromatosis Expression is Essential for Electroacupuncture-Mediated Alleviation of Neuroinflammatory Injury by Regulating Microglial Polarization in Rats Subjected to Focal Cerebral Ischemia/Reperfusion

Xing Lin,1 Jian Zhan,2 Jin Jiang,3 Yikun Ren3 1Department of Biological Immunotherapy, Chongqing University Cancer Hospital, Chongqing Cancer Institute, Chongqing Cancer Hospital, Shapingba District, Chongqing, 400030, People’s Republic of China; 2Department of Neurology, The Second Affili...

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Autores principales:	Lin X, Zhan J, Jiang J, Ren Y
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2021
Materias:	microglial polarization cerebral ischemia neuroinflammation cyld electroacupuncture nlrp3 inflammasome cx3cl1/cx3cr1 axis Pathology RB1-214 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/59fd377ef4c4417784097072583cba19
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spelling	oai:doaj.org-article:59fd377ef4c4417784097072583cba192021-12-02T14:44:23ZUpregulation of Neuronal Cylindromatosis Expression is Essential for Electroacupuncture-Mediated Alleviation of Neuroinflammatory Injury by Regulating Microglial Polarization in Rats Subjected to Focal Cerebral Ischemia/Reperfusion1178-7031https://doaj.org/article/59fd377ef4c4417784097072583cba192021-05-01T00:00:00Zhttps://www.dovepress.com/upregulation-of-neuronal-cylindromatosis-expression-is-essential-for-e-peer-reviewed-fulltext-article-JIRhttps://doaj.org/toc/1178-7031Xing Lin,1 Jian Zhan,2 Jin Jiang,3 Yikun Ren3 1Department of Biological Immunotherapy, Chongqing University Cancer Hospital, Chongqing Cancer Institute, Chongqing Cancer Hospital, Shapingba District, Chongqing, 400030, People’s Republic of China; 2Department of Neurology, The Second Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou Province, 563000, People’s Republic of China; 3Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaCorrespondence: Jin Jiang; Yikun RenThe First Affiliated Hospital of Chongqing Medical University, Yuzhong District, Chongqing, 400016, People’s Republic of ChinaTel +86 177 4992 3714; +86 151 9609 7005Email m17749923714@163.com; renyikunde@163.comBackground: Activated microglia are polarized into the M1 or M2 phenotype. We previously reported that electroacupuncture (EA) effectively prevented nuclear factor-κB (NF-κB) nuclear translocation and improved neuronal C-X-C motif 3 chemokine ligand 1 (CX3CL1) expression, repressing microglial activation by upregulating neuronal cylindromatosis (CYLD) expression in the periischemic cortex. However, the potential mechanisms are unclear. Therefore, we explored whether EA improved CYLD protein expression to regulate microglial polarization-mediated neuroinflammation and the potential mechanisms in an ischemic stroke model.Methods: A middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in male Sprague-Dawley (SD) rats. The rats were treated with EA at the Baihui, Hegu and Taichong acupoints once daily beginning 2 h after focal cerebral ischemia. CYLD gene interference was used to investigate the role of CYLD in microglial polarization. We used neurobehavioral evaluations and TTC staining to examine the neuroprotective effect of EA via CYLD upregulation. Immunofluorescence and RT-qPCR were used to measure NLRP3 activation, M1/M2 microglial activation, pro-/anti-inflammatory gene mRNA expression and crosstalk (CX3CL1/CX3CR1 axis) between neurons and microglia. Western blotting was used to assess the underlying molecular mechanism.Results: CYLD inhibited M1 microglial activation and improved M2 microglial activation after 72 h of reperfusion. CYLD overexpression decreased the NLRP3 mRNA level. CYLD suppressed microglial overactivation by inhibiting NLRP3 activation. CYLD gene silencing partially weakened EA improvement of neurological function deficits and reduction of infarct volumes after 72 h reperfusion. In addition, EA inhibited M1-like phenotypic microglial activation and promoted M2-like phenotypic microglia through upregulating CYLD expression. Finally, EA-mediated modulation of the CX3CL1/CX3CR1 axis and NLRP3 inflammasome was reversed by CYLD gene silencing in the periischemic cortex.Conclusion: EA-induced upregulation of neuronal CYLD expression plays anti-inflammatory and neuroprotective roles and regulates the interaction between neurons and microglia, thereby suppressing M1 and improving M2 microglial activation in the periischemic cortex.Keywords: microglial polarization, cerebral ischemia, neuroinflammation, CYLD, electroacupuncture, NLRP3 inflammasome, CX3CL1/CX3CR1 axisLin XZhan JJiang JRen YDove Medical Pressarticlemicroglial polarizationcerebral ischemianeuroinflammationcyldelectroacupuncturenlrp3 inflammasomecx3cl1/cx3cr1 axisPathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 14, Pp 2061-2078 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	microglial polarization cerebral ischemia neuroinflammation cyld electroacupuncture nlrp3 inflammasome cx3cl1/cx3cr1 axis Pathology RB1-214 Therapeutics. Pharmacology RM1-950
spellingShingle	microglial polarization cerebral ischemia neuroinflammation cyld electroacupuncture nlrp3 inflammasome cx3cl1/cx3cr1 axis Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Lin X Zhan J Jiang J Ren Y Upregulation of Neuronal Cylindromatosis Expression is Essential for Electroacupuncture-Mediated Alleviation of Neuroinflammatory Injury by Regulating Microglial Polarization in Rats Subjected to Focal Cerebral Ischemia/Reperfusion
description	Xing Lin,1 Jian Zhan,2 Jin Jiang,3 Yikun Ren3 1Department of Biological Immunotherapy, Chongqing University Cancer Hospital, Chongqing Cancer Institute, Chongqing Cancer Hospital, Shapingba District, Chongqing, 400030, People’s Republic of China; 2Department of Neurology, The Second Affiliated Hospital of Zunyi Medical College, Zunyi, Guizhou Province, 563000, People’s Republic of China; 3Department of Neurology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of ChinaCorrespondence: Jin Jiang; Yikun RenThe First Affiliated Hospital of Chongqing Medical University, Yuzhong District, Chongqing, 400016, People’s Republic of ChinaTel +86 177 4992 3714; +86 151 9609 7005Email m17749923714@163.com; renyikunde@163.comBackground: Activated microglia are polarized into the M1 or M2 phenotype. We previously reported that electroacupuncture (EA) effectively prevented nuclear factor-κB (NF-κB) nuclear translocation and improved neuronal C-X-C motif 3 chemokine ligand 1 (CX3CL1) expression, repressing microglial activation by upregulating neuronal cylindromatosis (CYLD) expression in the periischemic cortex. However, the potential mechanisms are unclear. Therefore, we explored whether EA improved CYLD protein expression to regulate microglial polarization-mediated neuroinflammation and the potential mechanisms in an ischemic stroke model.Methods: A middle cerebral artery occlusion/reperfusion (MCAO/R) model was established in male Sprague-Dawley (SD) rats. The rats were treated with EA at the Baihui, Hegu and Taichong acupoints once daily beginning 2 h after focal cerebral ischemia. CYLD gene interference was used to investigate the role of CYLD in microglial polarization. We used neurobehavioral evaluations and TTC staining to examine the neuroprotective effect of EA via CYLD upregulation. Immunofluorescence and RT-qPCR were used to measure NLRP3 activation, M1/M2 microglial activation, pro-/anti-inflammatory gene mRNA expression and crosstalk (CX3CL1/CX3CR1 axis) between neurons and microglia. Western blotting was used to assess the underlying molecular mechanism.Results: CYLD inhibited M1 microglial activation and improved M2 microglial activation after 72 h of reperfusion. CYLD overexpression decreased the NLRP3 mRNA level. CYLD suppressed microglial overactivation by inhibiting NLRP3 activation. CYLD gene silencing partially weakened EA improvement of neurological function deficits and reduction of infarct volumes after 72 h reperfusion. In addition, EA inhibited M1-like phenotypic microglial activation and promoted M2-like phenotypic microglia through upregulating CYLD expression. Finally, EA-mediated modulation of the CX3CL1/CX3CR1 axis and NLRP3 inflammasome was reversed by CYLD gene silencing in the periischemic cortex.Conclusion: EA-induced upregulation of neuronal CYLD expression plays anti-inflammatory and neuroprotective roles and regulates the interaction between neurons and microglia, thereby suppressing M1 and improving M2 microglial activation in the periischemic cortex.Keywords: microglial polarization, cerebral ischemia, neuroinflammation, CYLD, electroacupuncture, NLRP3 inflammasome, CX3CL1/CX3CR1 axis
format	article
author	Lin X Zhan J Jiang J Ren Y
author_facet	Lin X Zhan J Jiang J Ren Y
author_sort	Lin X
title	Upregulation of Neuronal Cylindromatosis Expression is Essential for Electroacupuncture-Mediated Alleviation of Neuroinflammatory Injury by Regulating Microglial Polarization in Rats Subjected to Focal Cerebral Ischemia/Reperfusion
title_short	Upregulation of Neuronal Cylindromatosis Expression is Essential for Electroacupuncture-Mediated Alleviation of Neuroinflammatory Injury by Regulating Microglial Polarization in Rats Subjected to Focal Cerebral Ischemia/Reperfusion
title_full	Upregulation of Neuronal Cylindromatosis Expression is Essential for Electroacupuncture-Mediated Alleviation of Neuroinflammatory Injury by Regulating Microglial Polarization in Rats Subjected to Focal Cerebral Ischemia/Reperfusion
title_fullStr	Upregulation of Neuronal Cylindromatosis Expression is Essential for Electroacupuncture-Mediated Alleviation of Neuroinflammatory Injury by Regulating Microglial Polarization in Rats Subjected to Focal Cerebral Ischemia/Reperfusion
title_full_unstemmed	Upregulation of Neuronal Cylindromatosis Expression is Essential for Electroacupuncture-Mediated Alleviation of Neuroinflammatory Injury by Regulating Microglial Polarization in Rats Subjected to Focal Cerebral Ischemia/Reperfusion
title_sort	upregulation of neuronal cylindromatosis expression is essential for electroacupuncture-mediated alleviation of neuroinflammatory injury by regulating microglial polarization in rats subjected to focal cerebral ischemia/reperfusion
publisher	Dove Medical Press
publishDate	2021
url	https://doaj.org/article/59fd377ef4c4417784097072583cba19
work_keys_str_mv	AT linx upregulationofneuronalcylindromatosisexpressionisessentialforelectroacupuncturemediatedalleviationofneuroinflammatoryinjurybyregulatingmicroglialpolarizationinratssubjectedtofocalcerebralischemiareperfusion AT zhanj upregulationofneuronalcylindromatosisexpressionisessentialforelectroacupuncturemediatedalleviationofneuroinflammatoryinjurybyregulatingmicroglialpolarizationinratssubjectedtofocalcerebralischemiareperfusion AT jiangj upregulationofneuronalcylindromatosisexpressionisessentialforelectroacupuncturemediatedalleviationofneuroinflammatoryinjurybyregulatingmicroglialpolarizationinratssubjectedtofocalcerebralischemiareperfusion AT reny upregulationofneuronalcylindromatosisexpressionisessentialforelectroacupuncturemediatedalleviationofneuroinflammatoryinjurybyregulatingmicroglialpolarizationinratssubjectedtofocalcerebralischemiareperfusion
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Upregulation of Neuronal Cylindromatosis Expression is Essential for Electroacupuncture-Mediated Alleviation of Neuroinflammatory Injury by Regulating Microglial Polarization in Rats Subjected to Focal Cerebral Ischemia/Reperfusion

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