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 remodelling, and leads to functional deficits. Effective treatments for SCI are not currently available. Maresin 1 (MaR1) is a highly conserved specialized pro-resolving mediators (SPM) hosting potent anti-inflammatory and pro-resolving 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 post-injury. Exogenous administration of MaR1, a highly conserved SPM, propagated inflammatory resolution after SCI, as revealed by accelerated clearance of neutrophils and the reduction in macrophage accumulation at the lesion site. In the search of mechanisms underlying the pro-resolving actions of MaR1 in SCI, we found that this SPM facilitated several hallmarks of resolution of inflammation, including reduction of pro-inflammatory cytokines (CXCL1, CXCL2, CCL3, CCL4, IL6, CSF3), silencing of major inflammatory intracellular signalling cascades (STAT1, STAT3, STAT5, p38, ERK1/2), redirection of macrophage activation towards a pro-repair phenotype, and increase of the phagocytic engulfment of neutrophils by macrophages. Interestingly, MaR1 administration significantly improved locomotor recovery and mitigated secondary injury progression in a clinical relevant model of SCI. These findings suggest that pro-resolution namely immunoresolvent therapies would be a novel approach to improve neurological recovery after acute spinal cord injury. SIGNIFICANT STATEMENT Inflammation is a protective response to injury or infection. In order 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 would healing, as it occurs after spinal cord injury. We report that inflammation after spinal cord injury is dysregulated, in part, due to inappropriate synthesis of pro-resolving lipid mediators. We demonstrate that the administration of the resolution agonist, referred to as maresin 1, after spinal cord injury actively propagates resolution processes at the lesion site and improves neurological outcomes. Maresin 1 is identified as interventional candidate to attenuate dysregulated lesional inflammation and to restore functional recovery after spinal cord injury.