Maresin-1 Ameliorates Inflammation and Prevents Disease Progression in Preclinical Model of Multiple Sclerosis

Document Type

Conference Proceeding

Publication Date

5-1-2023

Publication Title

Mult Scler J

Abstract

Background: Multiple sclerosis (MS) is one of the most common inflammatory and neurodegenerative diseases in young adults leading to a build-up of neurological defects with an irreversible disability. Unresolved inflammation represents the pathological hallmark of MS and several other autoimmune diseases, however current therapeutic options fail to adequately suppress the ongoing inflammation, resulting in inflammatory attacks that gradually increase in severity. Studies suggest that the endogenous mechanisms to resolve inflammation are intact but become defective in patients which result in deficiency of downstream metabolites, pro-resolving lipid mediators, leading to unresolved inflammation and a delay in the healing/repair process, thus resulting in disease progression and continued neuronal damage. Objectives: Docosahexaenoic acid (DHA) metabolism being defective in MS, we hypothesize that supplementation of downstream metabolite of DHA, maresin 1 (MaR1) will resolve inflammation and demyelination in preclinical animal model of MS, experimental allergic encephalomyelitis (EAE). Methods: We performed a comparative metabolite profiling using targeted metabolipidomics in serum samples from 29 relapsing-remitting (RRMS) patients and 29 age and gendermatched healthy controls (HC). For therapeutic effect of MaR1, we induced EAE in SJL mice, followed by intraperitoneal treatment with 300ng of MaR1 from day1 post-disease induction. We evaluated the effect on disease severity and inflammation by monitoring disease course of EAE, recall response by ELISA, cytokine expression analysis by qPCR and western blotting, and immune profiling by flow cytometry. Also, the neuroprotective effect of MaR1 through myelination was assessed by single molecule array (SIMOA) assay and histopathology. Statistical analysis was done using Graph-Pad Prism. Results: Metabolite profiling revealed significant imbalance (p<0.05) between inflammatory response and resolution process in MS, confirming the metabolic dysfunction of lipid mediators including MaR1. Restoration of MaR1 prevented disease progression and reduced disease severity in EAE by inhibiting the infiltration of immune cells (CD4+IL17+ and CD4+FNγ+) in CNS as shown by intracellular staining (P<0.001). Recall response showed that MaR1 significantly inhibited pro-inflammatory cytokine IL17 (P<0.01) and promoted IL10 and IL4 production (P<0.001). Also, MaR1 exerted neuroprotective effects as we found lower levels of NFL (P<0.01) in the serum of treated mice compared to untreated which was further confirmed by higher expression of MBP in brain from MaR1 treated group. Conclusions: Overall, our targeted metabolipidomics in MS patients identified MaR1 deficiency, whose supplementation exerts anti-inflammatory and neuroprotective effects in preclinical animal model, suggesting MaR1 could be a new therapeutic molecule in MS.

PubMed ID

Not assigned.

Volume

29

Issue

2

First Page

108

Last Page

109

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