HDAC3 inhibition ameliorates spinal cord injury by immunomodulation

Abstract Following spinal cord injury (SCI), the innate immune response of microglia and infiltrating macrophages clears up cellular debris and promotes tissue repair, but it also inflicts secondary injury from inflammatory responses. Immunomodulation aimed at maximizing the beneficial effects while...

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Autores principales:	Tomoharu Kuboyama, Shalaka Wahane, Yong Huang, Xiang Zhou, Jamie K. Wong, Andrew Koemeter-Cox, Michael Martini, Roland H. Friedel, Hongyan Zou
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/a10fe06ffb994a84ac85365b0b75d5d1
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spelling	oai:doaj.org-article:a10fe06ffb994a84ac85365b0b75d5d12021-12-02T11:52:19ZHDAC3 inhibition ameliorates spinal cord injury by immunomodulation10.1038/s41598-017-08535-42045-2322https://doaj.org/article/a10fe06ffb994a84ac85365b0b75d5d12017-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-08535-4https://doaj.org/toc/2045-2322Abstract Following spinal cord injury (SCI), the innate immune response of microglia and infiltrating macrophages clears up cellular debris and promotes tissue repair, but it also inflicts secondary injury from inflammatory responses. Immunomodulation aimed at maximizing the beneficial effects while minimizing the detrimental roles of the innate immunity may aid functional recovery after SCI. However, intracellular drivers of global reprogramming of the inflammatory gene networks in the innate immune cells are poorly understood. Here we show that SCI resulted in an upregulation of histone deacetylase 3 (HDAC3) in the innate immune cells at the injury site. Remarkably, blocking HDAC3 with a selective small molecule inhibitor shifted microglia/macrophage responses towards inflammatory suppression, resulting in neuroprotective phenotypes and improved functional recovery in SCI model. Mechanistically, HDAC3 activity is largely responsible for histone deacetylation and inflammatory responses of primary microglia to classic inflammatory stimuli. Our results reveal a novel function of HDAC3 inhibitor in promoting functional recovery after SCI by dampening inflammatory cytokines, thus pointing towards a new direction of immunomodulation for SCI repair.Tomoharu KuboyamaShalaka WahaneYong HuangXiang ZhouJamie K. WongAndrew Koemeter-CoxMichael MartiniRoland H. FriedelHongyan ZouNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tomoharu Kuboyama Shalaka Wahane Yong Huang Xiang Zhou Jamie K. Wong Andrew Koemeter-Cox Michael Martini Roland H. Friedel Hongyan Zou HDAC3 inhibition ameliorates spinal cord injury by immunomodulation
description	Abstract Following spinal cord injury (SCI), the innate immune response of microglia and infiltrating macrophages clears up cellular debris and promotes tissue repair, but it also inflicts secondary injury from inflammatory responses. Immunomodulation aimed at maximizing the beneficial effects while minimizing the detrimental roles of the innate immunity may aid functional recovery after SCI. However, intracellular drivers of global reprogramming of the inflammatory gene networks in the innate immune cells are poorly understood. Here we show that SCI resulted in an upregulation of histone deacetylase 3 (HDAC3) in the innate immune cells at the injury site. Remarkably, blocking HDAC3 with a selective small molecule inhibitor shifted microglia/macrophage responses towards inflammatory suppression, resulting in neuroprotective phenotypes and improved functional recovery in SCI model. Mechanistically, HDAC3 activity is largely responsible for histone deacetylation and inflammatory responses of primary microglia to classic inflammatory stimuli. Our results reveal a novel function of HDAC3 inhibitor in promoting functional recovery after SCI by dampening inflammatory cytokines, thus pointing towards a new direction of immunomodulation for SCI repair.
format	article
author	Tomoharu Kuboyama Shalaka Wahane Yong Huang Xiang Zhou Jamie K. Wong Andrew Koemeter-Cox Michael Martini Roland H. Friedel Hongyan Zou
author_facet	Tomoharu Kuboyama Shalaka Wahane Yong Huang Xiang Zhou Jamie K. Wong Andrew Koemeter-Cox Michael Martini Roland H. Friedel Hongyan Zou
author_sort	Tomoharu Kuboyama
title	HDAC3 inhibition ameliorates spinal cord injury by immunomodulation
title_short	HDAC3 inhibition ameliorates spinal cord injury by immunomodulation
title_full	HDAC3 inhibition ameliorates spinal cord injury by immunomodulation
title_fullStr	HDAC3 inhibition ameliorates spinal cord injury by immunomodulation
title_full_unstemmed	HDAC3 inhibition ameliorates spinal cord injury by immunomodulation
title_sort	hdac3 inhibition ameliorates spinal cord injury by immunomodulation
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/a10fe06ffb994a84ac85365b0b75d5d1
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HDAC3 inhibition ameliorates spinal cord injury by immunomodulation

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