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Maresin-1 promotes neuroprotection in relapsing remitting mouse model of multiple sclerosis

ABSTRACT: Multiple sclerosis (MS) is a prevalent inflammatory neurodegenerative disease in young people, causing neurological abnormalities and impairment. We investigated the effect of maresin 1 (MaR1) on the progression of disease in relapsing remitting form of experimental autoimmune encephalomyelitis (RR-EAE). Treatment with MaR1 in RR-EAE accelerated inflammation resolution, protected against neurological impairments, and delayed disease development by reducing immune cell infiltration (CD4+IL17+ and CD4+IFNg+) into the CNS. Furthermore, injection of MaR1 enhanced IL-10 production, primarily in macrophages and CD4+ cells. However, neutralizing IL-10 with an anti-IL-10 antibody eliminated MaR1's protective impact on RR-EAE, implying that IL-10 plays a role in MaR1's EAE protection. Metabolism is increasingly being recognized as a critical element controlling the effector activity of many immune cells. Our investigation found that, when compared to vehicle treatment, MaR1 administration significantly repaired the metabolic dysregulation seen in CD4+ cells, macrophages, and microglia in the treated group. Furthermore, MaR1 treatment restored defective efferocytosis in EAE mice, which was potentially facilitated by the induction of metabolic alterations in macrophages and microglia. MaR1 also preserved myelin in the EAE group and regulated O4+ oligodendrocyte metabolism by reversing metabolic dysregulation via increased mitochondrial activity and decreased glycolysis. Overall, in a preclinical MS animal model, MaR1 therapy has anti-inflammatory and neuroprotective properties. It also induced metabolic reprogramming in disease-associated cell types, increased efferocytosis, and maintained myelination. These findings suggest MaR1's potential as a novel therapeutic agent for MS and other autoimmune diseases

ORGANISM(S): Mus musculus

PROVIDER: GSE276812 | GEO | 2024/12/08

REPOSITORIES: GEO

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Project description:Vitamin D3 (VitD) insufficiency is postulated to represent a major modifiable risk factor for multiple sclerosis (MS). While low VitD levels strongly correlate with higher MS risk in white populations, this is not the case for other ethnic groups, suggesting the existence of a genetic component. Moreover, VitD supplementation studies in MS so far have not shown a consistent benefit. We sought to determine whether direct manipulation of VitD levels modulates central nervous system (CNS) autoimmune disease in a sex-by-genotype-dependent manner. To this end, we used a dietary model of VitD modulation, together with the autoimmune animal model of MS, experimental autoimmune encephalomyelitis (EAE). To assess the impact of genotype-by-VitD interactions on EAE susceptibility, we utilized a chromosome substitution (consomic) mouse model that incorporates the genetic diversity of wild-derived PWD/PhJ mice. High VitD was protective in EAE in female, but not male C57BL/6J (B6) mice, and had no effect in EAE-resistant PWD/PhJ (PWD) mice. EAE protection was accompanied by sex- and genotype-specific suppression of proinflammatory transcriptional programs in effector CD4 T effector cells, but not CD4 Treg cells. Decreased expression of proinflammatory genes was observed with high VitD in female CD4 T cells, specifically implicating a key role of MHC class II genes, interferon gamma, and Th1 cell-mediated neuroinflammation. In consomic strains, effects of VitD on EAE were also sex- and genotype-dependent, whereby high VitD: 1) was protective, 2) had no effect, and, 3) unexpectedly had disease-exacerbating effects. Systemic levels of 25(OH)D differed across consomic strains, with higher levels associated with EAE protection only in females. Analysis of expression of key known VitD metabolism genes between B6 and PWD mice revealed that their expression is genetically determined and sex-specific, and implicated Cyp27b1 and Vdr as candidate genes responsible for differential EAE responses to VitD modulation. Taken together, our results support the observation that the association between VitD status and MS susceptibility is genotype-dependent, and suggest that the outcome of VitD status in MS is determined by gene-by-sex interactions.

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Maresin-1 promotes neuroprotection in relapsing remitting mouse model of multiple sclerosis

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