Specialized Pro-Resolving Lipid Mediators: Emerging Therapeutic Candidates for Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is a neuroinflammatory disease in which unresolved and uncontrolled inflammation disrupts normal cellular homeostasis and leads to a pathological disease state. It has long been recognized that endogenously derived metabolic by-products of omega fatty acids, known as specialized pro-resolving lipid mediators (SPMs), are instrumental in resolving the pathologic inflammation. However, there is minimal data available on the functional status of SPMs in MS, despite the fact that MS presents a classical model of chronic inflammation. Studies to date indicate that dysfunction of the SPM biosynthetic pathway is responsible for their altered levels in patient-derived biofluids, which contributes to heightened inflammation and disease severity. Collectively, current findings suggest the contentious role of SPMs in MS due to variable outcomes in biological matrices across studies conducted so far, which could, in part, also be attributed to differences in population characteristics. It seems that SPMs have neuroprotective action on MS by exerting proresolving effects on brain microglia in its preclinical model; however, there are no reports demonstrating the direct effect of SPMs on oligodendrocytes or neurons. This reveals that "one size does not fit all" notion holds significance for MS in terms of the status of SPMs in other inflammatory conditions. The lack of clarity served as the impetus for this review, which is the first of its kind to summarize the relevant data regarding the role of SPMs in MS and the potential to target them for biomarker development and future alternative therapies for this disease. Understanding the mechanisms behind biological actions of SPMs as resolution mediators may prevent or even cure MS and other neurodegenerative pathologies.

Keywords: Autoimmune; Demyelination; Inflammation; Multiple sclerosis; Resolution; Specialized pro-resolving mediators; Therapeutics.

Fig. 1

Cellular events in acute inflammation and resolution. The barrier break that occurs through different insults encountered by the body activates the immune system which in turn triggers acute inflammation. This process is regulated by the production of pro-inflammatory mediators from activated immune cells. The classical mediators include cytokines, chemokines, and omega-6 fatty acid-derived eicosanoids. Both innate and adaptive immune responses are involved in propagating ongoing inflammation in response to different inflammatory igniters. The inflammatory process is resolved by an active intrinsic mechanism regulated by pro-resolving lipid mediators (lipoxins, resolvins, maresins, and protectins) derived from omega-6 and omega-3 fatty acids, collectively termed as specialized pro-resolving mediators (SPMs). SPMs promote the end-stage of inflammation by counter-regulating pro-inflammatory signals and mediators through regulation of leukocyte trafficking, polymorphonuclear neutrophil (PMN) recruitment, and monocyte recruitment. They promote macrophage-assisted phagocytosis and efferocytosis, which leads to the clearance of inflammatory exudate and restoration of cellular homeostasis. Unresolved inflammation leads to nonstop chronic inflammation and tissue damage that are the underlying causes for several inflammatory diseases

Fig. 2

Schematic outline of the biosynthetic pathways that generate resolution mediators from different fatty acid-derived substrates

Fig. 3

Uncontrolled and unresolved inflammation as the underlying causes of MS. The complex interactions between different triggers, including trauma, barrier break (skin cut, wound, and injury), stress, pathogenic attack, internal insults, and pro-inflammatory diet, elicit protective physiological inflammation. Ideally, inflammation is actively resolved by endogenous mediators to maintain cellular homeostasis; however, when there is failed resolution of the inflammation, this leads to a pathological state in which progressive tissue damage, including neurodegeneration, can occur and ultimately give rise to a pathological condition such as MS