Zahoor Insha, Nematullah Mohammad, Ahmed Mohammad Ejaz, Fatma Mena, Mir Sajad, Ayasolla Kamesh, Cerghet Mirela, Palaniyandi Suresh, Ceci Veronica, Carrera Giulia, Buttari Fabio, Centonze Diego, Mao-Draayer Yang, Rattan Ramandeep, Chiurchiù Valerio, Giri Shailendra
Department of Neurology, Henry Ford Health, Detroit, MI 48202, USA.
Division of Hypertension and Vascular Research, Department of Internal Medicine, Henry Ford Health, Detroit, MI 48202, USA.
bioRxiv. 2024 Jun 19:2023.09.25.559216. doi: 10.1101/2023.09.25.559216.
Multiple sclerosis (MS) is one of the most common inflammatory neurodegenerative diseases in young adults and causes neurological abnormalities and disability. We studied the effect of maresin 1 (MaR1) on the progression of disease in a relapsing-remitting form of experimental allergic encephalomyelitis (RR-EAE). Treatment with MaR1 in RR-EAE accelerated inflammation resolution, protected against neurological deficits, and delayed disease progression by decreasing immune cell infiltration (CD4+IL17+ and CD4+IFNγ+) into the CNS. Furthermore, the administration of MaR1 increased the production of IL-10, predominantly in macrophages and CD4+ cells. However, neutralizing IL-10 with an anti-IL-10 antibody abolished the protective effect of MaR1 on RR-EAE, suggesting that IL-10 plays a role in mediating the protective effect of MaR1 on EAE. Metabolism is rapidly becoming recognized as an important factor influencing the effector function of many immune cells. Using cutting-edge metabolic assays, our study revealed that compared with vehicle treatment, MaR1 treatment effectively restored the metabolic dysregulation observed in CD4+ cells, macrophages, and microglia in the treated group. Furthermore, MaR1 treatment reversed defective efferocytosis in EAE mice, which was potentially facilitated by the induction of metabolic alterations in macrophages and microglia. MaR1 treatment also protected myelin in the EAE group and regulated the metabolism of O4+ oligodendrocytes by restoring metabolic dysregulation through improved mitochondrial function and decreased glycolysis. Overall, in a preclinical MS animal model, MaR1 treatment produced anti-inflammatory and neuroprotective effects. It also triggered metabolic reprogramming in disease-associated cell types, accelerated efferocytosis, and preserved myelination. These data support that MaR1 has potential as a novel treatment agent for MS and other autoimmune diseases.
多发性硬化症（MS）是年轻成年人中最常见的炎症性神经退行性疾病之一，可导致神经功能异常和残疾。我们研究了maresin 1（MaR1）对复发缓解型实验性变应性脑脊髓炎（RR-EAE）疾病进展的影响。RR-EAE中用MaR1治疗可加速炎症消退，预防神经功能缺损，并通过减少免疫细胞（CD4+IL17+和CD4+IFNγ+）浸润到中枢神经系统来延缓疾病进展。此外，MaR1的给药增加了IL-10的产生，主要在巨噬细胞和CD4+细胞中。然而，用抗IL-10抗体中和IL-10消除了MaR1对RR-EAE的保护作用，表明IL-10在介导MaR1对EAE的保护作用中起作用。代谢正迅速被认为是影响许多免疫细胞效应功能的重要因素。使用前沿的代谢分析方法，我们的研究表明，与载体处理相比，MaR1处理有效地恢复了治疗组中CD4+细胞、巨噬细胞和小胶质细胞中观察到的代谢失调。此外，MaR1处理逆转了EAE小鼠中有缺陷的噬菌作用，这可能是通过诱导巨噬细胞和小胶质细胞中的代谢改变来促进的。MaR1处理还保护了EAE组中的髓鞘，并通过改善线粒体功能和减少糖酵解来恢复代谢失调，从而调节O4+少突胶质细胞的代谢。总体而言，在临床前MS动物模型中，MaR1处理产生了抗炎和神经保护作用。它还引发了疾病相关细胞类型中的代谢重编程，加速了噬菌作用，并保留了髓鞘形成。这些数据支持MaR1有潜力作为MS和其他自身免疫性疾病的新型治疗药物。
