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

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

SUBMITTER: Fakan B

PROVIDER: S-EPMC6358998 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Megalin is a large endocytic receptor with relevant functions during development and adult life. It is expressed at the apical surface of several epithelial cell types, including proximal tubule cells (PTCs) in the kidney, where it internalizes apolipoproteins, vitamins and hormones with their corresponding carrier proteins and signaling molecules. Despite the important physiological roles of megalin little is known about the regulation of its expression. By analyzing the human megalin promoter, we found three response elements for the peroxisomal proliferator-activated receptor (PPAR). The objective of this study was to test whether megalin expression is regulated by the PPARs. METHODOLOGY/PRINCIPAL FINDINGS: Treatment of epithelial cell lines with PPAR? or PPAR? ligands increased megalin mRNA and protein expression. The stimulation of megalin mRNA expression was blocked by the addition of specific PPAR? or PPAR? antagonists. Furthermore, PPAR bound to three PPAR response elements located in the megalin promoter, as shown by EMSA, and PPAR? and its agonist activated a luciferase construct containing a portion of the megalin promoter and the first response element. Accordingly, the activation of PPAR? and PPAR? enhanced megalin expression in mouse kidney. As previously observed, high concentrations of bovine serum albumin (BSA) decreased megalin in PTCs in vitro; however, PTCs pretreated with PPAR? and PPAR? agonists avoided this BSA-mediated reduction of megalin expression. Finally, we found that megalin expression was significantly inhibited in the PTCs of rats that were injected with BSA to induce tubulointerstitial damage and proteinuria. Treatment of these rats with PPAR? agonists counteracted the reduction in megalin expression and the proteinuria induced by BSA. CONCLUSIONS: PPAR?/? and their agonists positively control megalin expression. This regulation could have an important impact on several megalin-mediated physiological processes and on pathophysiologies such as chronic kidney disease associated with diabetes and hypertension, in which megalin expression is impaired.

Project description:Ligand activation of peroxisome proliferator-activated receptors (PPARs) prevents cardiac myocyte hypertrophy, and we previously reported that diacylglycerol kinase zeta (DGKζ) is critically involved. DGKζ is an intracellular lipid kinase that catalyzes phosphorylation of diacylglycerol; by attenuating DAG signaling, DGKζ suppresses protein kinase C (PKC) and G-protein signaling. Here, we investigated how PPAR-DGKζ signaling blocks activation of the hypertrophic gene program. We focused on export of histone deacetylase 5 (HDAC5) from the nucleus, a key event during hypertrophy, since crosstalk occurs between PPARs and other members of the HDAC family. Using cardiac myocytes isolated from Sprague-Dawley rats, we determined that liganded PPARs disrupt endothelin-1 (ET1)-induced nuclear export of HDAC5 in a manner that is dependent on DGKζ. When DGKζ-mediated PKC inhibition was circumvented using a constitutively-active PKCε mutant, PPARs failed to block ET1-induced nuclear retention of HDAC5. Liganded PPARs also prevented (i) activation of protein kinase D (the downstream effector of PKC), (ii) HDAC5 phosphorylation at 14-3-3 protein chaperone binding sites (serines 259 and 498), and (iii) physical interaction between HDAC5 and 14-3-3, all of which are consistent with blockade of nucleo-cytoplasmic shuttling of HDAC5. Finally, the ability of PPARs to prevent neutralization of HDAC5 activity was associated with transcriptional repression of hypertrophic genes. This occurred by first, reduced MEF2 transcriptional activity and second, augmented deacetylation of histone H3 associated with hypertrophic genes expressing brain natriuretic peptide, β-myosin heavy chain, skeletal muscle α-actin, and cardiac muscle α-actin. Our findings identify spatial regulation of HDAC5 as a target for liganded PPARs, and to our knowledge, are the first to describe a mechanistic role for nuclear DGKζ in cardiac myocytes. In conclusion, these results implicate modulation of HDAC5 as a mechanism by which liganded PPARs suppress the hypertrophic gene program.

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

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