The effects of myelin on macrophage activation are phenotypic specific via cPLA2 in the context of spinal cord injury inflammation

Abstract Spinal cord injury (SCI) produces chronic, pro-inflammatory macrophage activation that impairs recovery. The mechanisms driving this chronic inflammation are not well understood. Here, we detail the effects of myelin debris on macrophage physiology and demonstrate a novel, activation state-...

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Autores principales:	Timothy J. Kopper, Bei Zhang, William M. Bailey, Kara E. Bethel, John C. Gensel
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/bcfad03edf464c22889b0e20e459344f
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spelling	oai:doaj.org-article:bcfad03edf464c22889b0e20e459344f2021-12-02T13:18:08ZThe effects of myelin on macrophage activation are phenotypic specific via cPLA2 in the context of spinal cord injury inflammation10.1038/s41598-021-85863-62045-2322https://doaj.org/article/bcfad03edf464c22889b0e20e459344f2021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-85863-6https://doaj.org/toc/2045-2322Abstract Spinal cord injury (SCI) produces chronic, pro-inflammatory macrophage activation that impairs recovery. The mechanisms driving this chronic inflammation are not well understood. Here, we detail the effects of myelin debris on macrophage physiology and demonstrate a novel, activation state-dependent role for cytosolic phospholipase-A2 (cPLA2) in myelin-mediated potentiation of pro-inflammatory macrophage activation. We hypothesized that cPLA2 and myelin debris are key mediators of persistent pro-inflammatory macrophage responses after SCI. To test this, we examined spinal cord tissue 28-days after thoracic contusion SCI in 3-month-old female mice and observed both cPLA2 activation and intracellular accumulation of lipid-rich myelin debris in macrophages. In vitro, we utilized bone marrow-derived macrophages to determine myelin’s effects across a spectrum of activation states. We observed phenotype-specific responses with myelin potentiating only pro-inflammatory (LPS + INF-γ; M1) macrophage activation, whereas myelin did not induce pro-inflammatory responses in unstimulated or anti-inflammatory (IL-4; M2) macrophages. Specifically, myelin increased levels of pro-inflammatory cytokines, reactive oxygen species, and nitric oxide production in M1 macrophages as well as M1-mediated neurotoxicity. PACOCF3 (cPLA2 inhibitor) blocked myelin’s detrimental effects. Collectively, we provide novel spatiotemporal evidence that myelin and cPLA2 play an important role in the pathophysiology of SCI inflammation and the phenotype-specific response to myelin implicate diverse roles of myelin in neuroinflammatory conditions.Timothy J. KopperBei ZhangWilliam M. BaileyKara E. BethelJohn C. GenselNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Timothy J. Kopper Bei Zhang William M. Bailey Kara E. Bethel John C. Gensel The effects of myelin on macrophage activation are phenotypic specific via cPLA2 in the context of spinal cord injury inflammation
description	Abstract Spinal cord injury (SCI) produces chronic, pro-inflammatory macrophage activation that impairs recovery. The mechanisms driving this chronic inflammation are not well understood. Here, we detail the effects of myelin debris on macrophage physiology and demonstrate a novel, activation state-dependent role for cytosolic phospholipase-A2 (cPLA2) in myelin-mediated potentiation of pro-inflammatory macrophage activation. We hypothesized that cPLA2 and myelin debris are key mediators of persistent pro-inflammatory macrophage responses after SCI. To test this, we examined spinal cord tissue 28-days after thoracic contusion SCI in 3-month-old female mice and observed both cPLA2 activation and intracellular accumulation of lipid-rich myelin debris in macrophages. In vitro, we utilized bone marrow-derived macrophages to determine myelin’s effects across a spectrum of activation states. We observed phenotype-specific responses with myelin potentiating only pro-inflammatory (LPS + INF-γ; M1) macrophage activation, whereas myelin did not induce pro-inflammatory responses in unstimulated or anti-inflammatory (IL-4; M2) macrophages. Specifically, myelin increased levels of pro-inflammatory cytokines, reactive oxygen species, and nitric oxide production in M1 macrophages as well as M1-mediated neurotoxicity. PACOCF3 (cPLA2 inhibitor) blocked myelin’s detrimental effects. Collectively, we provide novel spatiotemporal evidence that myelin and cPLA2 play an important role in the pathophysiology of SCI inflammation and the phenotype-specific response to myelin implicate diverse roles of myelin in neuroinflammatory conditions.
format	article
author	Timothy J. Kopper Bei Zhang William M. Bailey Kara E. Bethel John C. Gensel
author_facet	Timothy J. Kopper Bei Zhang William M. Bailey Kara E. Bethel John C. Gensel
author_sort	Timothy J. Kopper
title	The effects of myelin on macrophage activation are phenotypic specific via cPLA2 in the context of spinal cord injury inflammation
title_short	The effects of myelin on macrophage activation are phenotypic specific via cPLA2 in the context of spinal cord injury inflammation
title_full	The effects of myelin on macrophage activation are phenotypic specific via cPLA2 in the context of spinal cord injury inflammation
title_fullStr	The effects of myelin on macrophage activation are phenotypic specific via cPLA2 in the context of spinal cord injury inflammation
title_full_unstemmed	The effects of myelin on macrophage activation are phenotypic specific via cPLA2 in the context of spinal cord injury inflammation
title_sort	effects of myelin on macrophage activation are phenotypic specific via cpla2 in the context of spinal cord injury inflammation
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/bcfad03edf464c22889b0e20e459344f
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The effects of myelin on macrophage activation are phenotypic specific via cPLA2 in the context of spinal cord injury inflammation

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