Maresin 1 Promotes Inflammatory Resolution, Neuroprotection, and Functional Neurological Recovery After Spinal Cord Injury
Maresin 1 Promotes Inflammatory Resolution, Neuroprotection, and Functional Neurological Recovery After Spinal Cord Injury
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DOI：
10.1523/jneurosci.1395-17.2017
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发表时间：
2017-11-29
影响因子：
5.3
通讯作者：
Lopez-Vales, Ruben
中科院分区：
文献类型：
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作者：
Francos-Quijorna, Isaac;Santos-Nogueira, Eva;Lopez-Vales, Ruben
脊髓损伤（SCI）后炎症的消退是有缺陷的，这损害了组织的完整性和重塑，并导致功能缺陷。目前还没有有效的SCI药物治疗方法。Maresin 1（MaR 1）是一种高度保守的特化促消退介质（SPM），具有强效的抗炎和促消退特性，具有强效的组织再生作用。在这里，我们提供的证据表明，不适当的生物合成的SPM在损伤的脊髓阻碍了炎症的决议，并导致有害后果的神经功能的结果在成年雌性小鼠。我们报告，成年雌性小鼠脊髓挫伤后，SPM的生物合成在损伤部位不诱导达2周后受伤。外源性给予MaR 1（一种高度保守的SPM）可促进SCI后炎症消退，这可通过加速中性粒细胞清除和减少损伤部位的巨噬细胞蓄积来揭示。在研究MaR 1在SCI中促缓解作用的潜在机制时，我们发现这种SPM促进了炎症缓解的几个标志，包括促炎细胞因子的减少（CXCL 1、CXCL 2、CCL 3、CCL 4、IL 6和CSF 3），主要炎性细胞内信号级联的沉默（STAT 1、STAT 3、STAT 5、p38和ERK 1/2），巨噬细胞活化向修复前表型的重定向，以及巨噬细胞对中性粒细胞的吞噬吞噬的增加。有趣的是，在临床相关的SCI模型中，MaR 1给药显著改善了运动恢复并减轻了继发性损伤进展。这些研究结果表明，促消退，免疫治疗构成了一种新的方法，以改善急性SCI后的神经恢复。
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.