Exploiting the Therapeutic Potential of Endogenous Immunomodulatory Systems in Multiple Sclerosis—Special Focus on the Peroxisome Proliferator-Activated Receptors (PPARs) and the Kynurenines

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), PPAR gamma coactivator-1alpha (PGC-1 alpha), and kynurenine pathway metabolites. Although all PPARs ameliorate experimental autoimmune encephalomyelitis (EAE), recent evidence suggests that PPAR alpha, PPAR beta/delta agonists have less pronounced immunomodulatory effects and, along with PGC-1 alpha, are not biomarkers of neuroinflammation in contrast to PPAR gamma. Small clinical trials with PPAR gamma agonists have been published with positive results. Proposed as immunomodulatory and neuroprotective, the therapeutic use of PGC-1 alpha 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.