Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after Spinal Cord Injury

Resolution of inflammation is defective after spinal cord injury (SCI), which impairs tissue integrity and remodeling and leads to functional deficits. Effective pharmacological treatments for SCI are not currently available. Maresin 1 (MaR1) is a highly conserved specialized proresolving mediator (...

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Authors: Francos Quijorna, Isaac|||0000-0003-2514-4206, Santos Nogueira, Eva|||0000-0002-5917-3534, Gronert, Karsten, Sullivan, Aaron B., Kopp, Marcel A., Brommer, Benedikt, David, Samuel, Schwab, Jan M., López Vales, Rubén|||0000-0001-7615-9550
Format: article
Publication Date:2017
Country:España
Institution:Universitat Autònoma de Barcelona
Repository:Dipòsit Digital de Documents de la UAB
Language:English
OAI Identifier:oai:ddd.uab.cat:182705
Online Access:https://ddd.uab.cat/record/182705
https://dx.doi.org/urn:doi:10.1523/JNEUROSCI.1395-17.2017
Access Level:Open access
Keyword:Maresin-1
Lipid mediators
Neuroprotection
Resolution
Spinal cord injury
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spelling Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after Spinal Cord InjuryFrancos Quijorna, Isaac|||0000-0003-2514-4206Santos Nogueira, Eva|||0000-0002-5917-3534Gronert, KarstenSullivan, Aaron B.Kopp, Marcel A.Brommer, BenediktDavid, SamuelSchwab, Jan M.López Vales, Rubén|||0000-0001-7615-9550Maresin-1Lipid mediatorsNeuroprotectionResolutionSpinal cord injuryResolution of inflammation is defective after spinal cord injury (SCI), which impairs tissue integrity and remodeling and leads to functional deficits. Effective pharmacological treatments for SCI are not currently available. Maresin 1 (MaR1) is a highly conserved specialized proresolving mediator (SPM) hosting potent anti-inflammatory and proresolving properties with potent tissue regenerative actions. Here, we provide evidence that the inappropriate biosynthesis of SPM in the lesioned spinal cord hampers the resolution of inflammation and leads to deleterious consequences on neurological outcome in adult female mice. We report that, after spinal cord contusion injury in adult female mice, the biosynthesis of SPM is not induced in the lesion site up to 2 weeks after injury. Exogenous administration of MaR1, a highly conserved SPM, propagated inflammatory resolution after SCI, as revealed by accelerated clearance of neutrophils and a reduction in macrophage accumulation at the lesion site. In the search of mechanisms underlying the proresolving actions of MaR1 in SCI, we found that this SPM facilitated several hallmarks of resolution of inflammation, including reduction of proinflammatory cytokines (CXCL1, CXCL2, CCL3, CCL4, IL6, and CSF3), silencing of major inflammatory intracellular signaling cascades (STAT1, STAT3, STAT5, p38, and ERK1/2), redirection of macrophage activation toward a prorepair phenotype, and increase of the phagocytic engulfment of neutrophils by macrophages. Interestingly, MaR1 administration improved locomotor recovery significantly and mitigated secondary injury progression in a clinical relevant model of SCI. These findings suggest that proresolution, immunoresolvent therapies constitute a novel approach to improving neurological recovery after acute SCI.SIGNIFICANCE STATEMENT Inflammation is a protective response to injury or infection. To result in tissue homeostasis, inflammation has to resolve over time. Incomplete or delayed resolution leads to detrimental effects, including propagated tissue damage and impaired wound healing, as occurs after spinal cord injury (SCI). We report that inflammation after SCI is dysregulated in part due to inappropriate synthesis of proresolving lipid mediators. We demonstrate that the administration of the resolution agonist referred to as maresin 1 (MaR1) after SCI actively propagates resolution processes at the lesion site and improves neurological outcome. MaR1 is identified as an interventional candidate to attenuate dysregulated lesional inflammation and to restore functional recovery after SCI. 22017-01-0120172017-01-01Articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://ddd.uab.cat/record/182705https://dx.doi.org/urn:doi:10.1523/JNEUROSCI.1395-17.2017reponame:Dipòsit Digital de Documents de la UABinstname:Universitat Autònoma de BarcelonaInglésengMinisterio de Ciencia e Innovación https://doi.org/10.13039/501100004837 SAF2010-17851Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 SAF2013-48431open accesshttp://purl.org/coar/access_right/c_abf2Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:ddd.uab.cat:1827052026-06-06T12:50:31Z
dc.title.none.fl_str_mv Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after Spinal Cord Injury
title Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after Spinal Cord Injury
spellingShingle Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after Spinal Cord Injury
Francos Quijorna, Isaac|||0000-0003-2514-4206
Maresin-1
Lipid mediators
Neuroprotection
Resolution
Spinal cord injury
title_short Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after Spinal Cord Injury
title_full Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after Spinal Cord Injury
title_fullStr Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after Spinal Cord Injury
title_full_unstemmed Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after Spinal Cord Injury
title_sort Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after Spinal Cord Injury
dc.creator.none.fl_str_mv Francos Quijorna, Isaac|||0000-0003-2514-4206
Santos Nogueira, Eva|||0000-0002-5917-3534
Gronert, Karsten
Sullivan, Aaron B.
Kopp, Marcel A.
Brommer, Benedikt
David, Samuel
Schwab, Jan M.
López Vales, Rubén|||0000-0001-7615-9550
author Francos Quijorna, Isaac|||0000-0003-2514-4206
author_facet Francos Quijorna, Isaac|||0000-0003-2514-4206
Santos Nogueira, Eva|||0000-0002-5917-3534
Gronert, Karsten
Sullivan, Aaron B.
Kopp, Marcel A.
Brommer, Benedikt
David, Samuel
Schwab, Jan M.
López Vales, Rubén|||0000-0001-7615-9550
author_role author
author2 Santos Nogueira, Eva|||0000-0002-5917-3534
Gronert, Karsten
Sullivan, Aaron B.
Kopp, Marcel A.
Brommer, Benedikt
David, Samuel
Schwab, Jan M.
López Vales, Rubén|||0000-0001-7615-9550
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Maresin-1
Lipid mediators
Neuroprotection
Resolution
Spinal cord injury
topic Maresin-1
Lipid mediators
Neuroprotection
Resolution
Spinal cord injury
description Resolution of inflammation is defective after spinal cord injury (SCI), which impairs tissue integrity and remodeling and leads to functional deficits. Effective pharmacological treatments for SCI are not currently available. Maresin 1 (MaR1) is a highly conserved specialized proresolving mediator (SPM) hosting potent anti-inflammatory and proresolving properties with potent tissue regenerative actions. Here, we provide evidence that the inappropriate biosynthesis of SPM in the lesioned spinal cord hampers the resolution of inflammation and leads to deleterious consequences on neurological outcome in adult female mice. We report that, after spinal cord contusion injury in adult female mice, the biosynthesis of SPM is not induced in the lesion site up to 2 weeks after injury. Exogenous administration of MaR1, a highly conserved SPM, propagated inflammatory resolution after SCI, as revealed by accelerated clearance of neutrophils and a reduction in macrophage accumulation at the lesion site. In the search of mechanisms underlying the proresolving actions of MaR1 in SCI, we found that this SPM facilitated several hallmarks of resolution of inflammation, including reduction of proinflammatory cytokines (CXCL1, CXCL2, CCL3, CCL4, IL6, and CSF3), silencing of major inflammatory intracellular signaling cascades (STAT1, STAT3, STAT5, p38, and ERK1/2), redirection of macrophage activation toward a prorepair phenotype, and increase of the phagocytic engulfment of neutrophils by macrophages. Interestingly, MaR1 administration improved locomotor recovery significantly and mitigated secondary injury progression in a clinical relevant model of SCI. These findings suggest that proresolution, immunoresolvent therapies constitute a novel approach to improving neurological recovery after acute SCI.SIGNIFICANCE STATEMENT Inflammation is a protective response to injury or infection. To result in tissue homeostasis, inflammation has to resolve over time. Incomplete or delayed resolution leads to detrimental effects, including propagated tissue damage and impaired wound healing, as occurs after spinal cord injury (SCI). We report that inflammation after SCI is dysregulated in part due to inappropriate synthesis of proresolving lipid mediators. We demonstrate that the administration of the resolution agonist referred to as maresin 1 (MaR1) after SCI actively propagates resolution processes at the lesion site and improves neurological outcome. MaR1 is identified as an interventional candidate to attenuate dysregulated lesional inflammation and to restore functional recovery after SCI.
publishDate 2017
dc.date.none.fl_str_mv 2
2017-01-01
2017
2017-01-01
dc.type.none.fl_str_mv Article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://ddd.uab.cat/record/182705
https://dx.doi.org/urn:doi:10.1523/JNEUROSCI.1395-17.2017
url https://ddd.uab.cat/record/182705
https://dx.doi.org/urn:doi:10.1523/JNEUROSCI.1395-17.2017
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv Ministerio de Ciencia e Innovación https://doi.org/10.13039/501100004837 SAF2010-17851
Ministerio de Economía y Competitividad https://doi.org/10.13039/501100003329 SAF2013-48431
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.source.none.fl_str_mv reponame:Dipòsit Digital de Documents de la UAB
instname:Universitat Autònoma de Barcelona
instname_str Universitat Autònoma de Barcelona
reponame_str Dipòsit Digital de Documents de la UAB
collection Dipòsit Digital de Documents de la UAB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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