Abstract
Multiple sclerosis (MS) is a progressive neurodegenerative disease, characterized by autoimmune central nervous system (CNS) demyelination attributable to a disturbed balance between encephalitic T helper 1 (Th1) and T helper 17 (Th17) and immunomodulatory regulatory T cell (Treg) and T helper 2 (Th2) cells, and an alternatively activated macrophage (M2) excess. Endogenous molecular systems regulating these inflammatory processes have recently been investigated to identify molecules that can potentially influence the course of the disease. These include the peroxisome proliferator-activated receptors (PPARs), PPARγ coactivator-1alpha (PGC-1α), and kynurenine pathway metabolites. Although all PPARs ameliorate experimental autoimmune encephalomyelitis (EAE), recent evidence suggests that PPARα, PPARβ/δ agonists have less pronounced immunomodulatory effects and, along with PGC-1α, are not biomarkers of neuroinflammation in contrast to PPARγ. Small clinical trials with PPARγ agonists have been published with positive results. Proposed as immunomodulatory and neuroprotective, the therapeutic use of PGC-1α activation needs to be assessed in EAE/MS. The activation of indolamine 2,3-dioxygenase (IDO), the rate-limiting step of the kynurenine pathway of tryptophan (Trp) metabolism, plays crucial immunomodulatory roles. Indeed, Trp metabolites have therapeutic relevance in EAE and drugs with structural analogy to kynurenines, such as teriflunomide, are already approved for MS. Further studies are required to gain deeper knowledge of such endogenous immunomodulatory pathways with potential therapeutic implications in MS.
Highlights
Multiple sclerosis (MS) is a chronic progressive neuroinflammatory and neurodegenerative disease, characterized by demyelination, and axonal and neuronal degeneration in the central nervous system (CNS), mediated in part by target-specific autoimmune processes [1]
In addition to the direct cytotoxicity exerted on myelin-producing oligodendrocytes and demyelinated axons, this process leads to astrocyte activation, which plays a dual role in MS, as reactive astrocytes both stimulate and restrain inflammation and tissue damage [19], in part by increasing the leakage of the blood-brain barrier (BBB) and by secreting immunosuppressive molecules, respectively [20]
This review summarizes the current state of knowledge about certain endogenous molecular pathways with the potential ability to influence the pathogenesis and/or course of MS, with special emphasis on peroxisome proliferator-activated receptors (PPARs), PPARγ coactivator-1alpha (PGC-1α), and the kynurenines
Summary
Multiple sclerosis (MS) is a chronic progressive neuroinflammatory and neurodegenerative disease, characterized by demyelination, and axonal and neuronal degeneration in the central nervous system (CNS), mediated in part by target-specific autoimmune processes [1]. A number of different endogenous molecular systems have been implicated in the regulation of such autoaggressive processes by promoting a shift from the encephalitogenic/demyelinating phenotype of the immune response (i.e., Th1, Th17, and M1 cells) to enable repressive and restorative responses (i.e., mediated by Th2, Treg, and M2), serving as innate suppressors of target-specific immunity The recognition of such processes is significant, first as the increased expression/production of their contributors may serve as biomarkers with clinical relevance in different body compartments (i.e., prognostic biomarkers or indicators of a therapeutic effect in the blood or cerebrospinal fluid (CSF)), and their manipulation might provide novel therapeutic targets and soil for future research and drug development. Reviews and original research reports were both considered along with relevant references originally undetected by the search engine, but cited within the identified publications
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