Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after Spinal Cord Injury
Francos Quijorna, Isaac (Universitat Autònoma de Barcelona. Institut de Neurociències)
Santos Nogueira, Eva (Universitat Autònoma de Barcelona. Institut de Neurociències)
Gronert, Karsten (University of California (Berkeley))
Sullivan, Aaron B. (University of California (Berkeley))
Kopp, Marcel A. (Charité - Universitätsmedizin Berlin)
Brommer, Benedikt (Charité - Universitätsmedizin Berlin)
David, Samuel (McGill University Health Centre (Montreal, Canadà))
Schwab, Jan M. (Charité - Universitätsmedizin Berlin)
López Vales, Rubén (Universitat Autònoma de Barcelona. Institut de Neurociències)

Data:	2017
Resum:	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.
Ajuts:	Ministerio de Economía y Competitividad SAF2010-17851 Ministerio de Economía y Competitividad SAF2013-48431
Drets:	Aquest 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.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Maresin-1 ; Lipid mediators ; Neuroprotection ; Resolution ; Spinal cord injury
Publicat a:	The Journal of neuroscience, Vol. 37, Núm. 48 (November 2017) , p. 11731-11743, ISSN 1529-2401

DOI: 10.1523/JNEUROSCI.1395-17.2017
PMID: 29109234

13 p, 3.3 MB

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