Maresin-1 promotes neuroprotection and prevents disease progression in experimental models of multiple sclerosis through metabolic reprogramming and shaping innate and adaptive disease-associated cell types

Abstract

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+IFN{gamma}+) 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. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/559216v2_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@10b8a0aorg.highwire.dtl.DTLVardef@93bbfdorg.highwire.dtl.DTLVardef@11ae998org.highwire.dtl.DTLVardef@1de3324_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMaR1 expedited inflammation resolution and prevented neurological impairments in RR-EAE. C_LIO_LIIL-10 plays a role in mediating the protective effect of MaR1 on EAE. C_LIO_LIMaR1 repaired CD4, macrophage, and microglia metabolic abnormalities. C_LIO_LIMaR1 therapy restored efferocytosis in EAE. C_LIO_LIMaR1 preserved myelin and improved O4+ oligodendrocyte metabolism. C_LI