Resolution Failure in Multiple Sclerosis: Linking Lipid Mediators to Neuroinflammation and Disease Progression

Multiple sclerosis (MS) is a chronic immune-mediated and neurodegenerative disorder of the central nervous system characterized by highly heterogeneous clinical courses and progressive accumulation of disability. Traditionally viewed as a relapsing inflammatory disease driven by peripheral autoimmunity, emerging evidence instead supports a continuum in which early immune attacks evolve into compartmentalized, chronic "smoldering" pathology that persists independently of overt relapses. This chapter integrates current knowledge of MS pathogenesis, focusing on the central emerging concept that MS reflects a fundamental failure of inflammation resolution. Specialized pro-resolving mediators (SPMs), which normally terminate inflammation and promote tissue repair, are consistently dysregulated in experimental and human MS. Preclinical studies demonstrate that SPMs such as resolvins, lipoxins, and maresins reduce neuroinflammation, prevent demyelination, and restore immune balance, while human metabolipidomic data reveal systemic deficiencies in pro-resolving lipid pathways alongside enrichment of pro-inflammatory eicosanoids. At the cellular level, SPMs modulate both innate and adaptive immune responses, stabilize blood-brain barrier integrity, and promote reparative phenotypes; however, reduced responsiveness in MS-derived cells suggests combined defects in mediator availability and signaling capacity.Collectively, these findings reposition MS as a disorder of defective resolution biology rather than solely excessive inflammation. This framework unifies relapsing and progressive disease mechanisms and provides a rationale for therapeutic strategies aimed at restoring endogenous resolution pathways. Nevertheless, key questions remain regarding the origin of resolution failure, its stage-specific dynamics, and the translational efficacy of SPM-based interventions in humans.