Pro-resolution lipid mediator maresin-1 ameliorates inflammation, promotes neuroprotection, and prevents disease progression in experimental models of multiple sclerosis

Abstract

AbstractMultiple sclerosis (MS) is the most common inflammatory neurodegenerative disease in young adults, resulting in neurological defects and disability. The endogenous mechanisms to resolve inflammation are intact but become defective in patients, resulting in lack of resolution mediators and unresolved chronic inflammation. Docosahexaenoic acid (DHA) metabolism being impaired in MS, we hypothesize that supplementing its downstream metabolite maresin 1 (MaR1) will alleviate inflammation and demyelination in preclinical mouse model of MS; experimental allergic encephalomyelitis (EAE). Restoration of MaR1 by its exogenous administration in EAE mice propagated inflammatory resolution and had a protective effect on neurological deficits, prevented disease progression, and reduced disease severity by reducing immune cell infiltration (CD4+IL17+ and CD4+IFN-γ+) into the CNS. It significantly reduced the proinflammatory cytokine IL17 and promoted an anti-inflammatory response via IL10 and IL4. Neutralization of IL10 abolished the protective effect of MaR1 in EAE confirming IL10 is mediating MaR1 effect in EAE. Furthermore, it improved the pathophysiology and exerted neuroprotective effects by mitigating disease signs in EAE as evidenced by lower levels of NFL in the plasma of treated group compared to control and higher MBP expression in the brain from the MaR1 treated mice, decreased inflammatory infiltrates, and less demyelination and vacuolization in the spinal cord tissue sections of treated mice. SCENITH data confirmed that MaR1 maintains myelin by regulating oligodendrocyte metabolism. Also, it induces metabolic reprogramming in infiltrating CD4 cells and macrophages, which modulate their phenotype. Metabolic changes induced macrophages by MaR1 restores the impaired efferocytosis in EAE, promoting clearance of damaged myelin and dead cells; thereby lowering the disability with disease course. Overall, MaR1 supplementation has anti-inflammatory and neuroprotective effects in preclinical animal models and induces metabolic reprogramming in disease associated cell-types, promotes efferocytosis, implying that it could be a new therapeutic molecule in MS and other autoimmune diseases.HighlightsInflammation is dysregulated in EAE due to impaired synthesis of DHA derived proresolving lipid mediator MaR1.Administration of the resolution agonist MaR1 propagates resolution processes and improves neurological outcome in RR model of EAE.MaR1 ameliorates clinical signs of EAE by attenuating pro-inflammatory cytokine IL17 mediated response and promoting anti-inflammatory response through IL10.MaR1 supplementation improves the pathophysiology in EAE and shows neuroprotection as indicated by the lower levels of NFL in the plasma and higher expression of MBP in the brain of treated mice.MaR1 induces metabolic reprogramming in disease-associated cell types.MaR1 promotes efferocytosis in EAE through metabolic reprogramming of macrophages.SignificanceInflammatory process is a protective response to several challenges like injury or infection. However, it must resolve over time to maintain tissue homeostasis. Impaired or delayed resolution leads to damaging effects, including chronic inflammation, tissue damage, and disease progression as occurs in multiple sclerosis (MS). We report that inflammation is dysregulated in preclinical animal model of MS, experimental autoimmune encephalomyelitis (EAE), partially due to impaired synthesis of proresolving lipid mediators. We show that the administration of the resolution agonist known as maresin 1 (MaR1) in EAE actively propagates resolution processes and improves neurological outcome. We conclude that MaR1 is a potential interventional candidate to attenuate dysregulated inflammation and to restore neurological deficits in EAE.Graphical abstract