TNFα downregulates PPARδ expression in oligodendrocyte progenitor cells: Implications for demyelinating diseases

Abstract

TNFalpha has been implicated in several demyelinating disorders, including multiple sclerosis (MS) and X-adrenoleukodystrophy (X-ALD). TNFalpha abundance is greatly increased in the areas surrounding damaged regions of the central nervous system of patients with MS and X-ALD, but its role in the observed demyelination remains to be elucidated. A class of nuclear receptors, the peroxisome proliferator-activated receptors (PPARs), has been implicated in several physiological and pathological processes. In particular, PPARdelta has been shown to promote oligodendrocyte (OL) survival and differentiation and PPARgamma has been implicated in inflammation. In the present study, we investigate on the effects of TNFalpha on OLs during differentiation in vitro. The results obtained show that TNFalpha treatment impairs PPARdelta expression with concomitant decrease of lignocerolyl-CoA synthase and very-long-chain fatty acid beta-oxidation as well as plasmalogen biosynthesis. We propose a hypothetical model possibly explaining the perturbation effects of proinflammatory cytokines on myelin synthesis, maturation, and turnover.

Gemfibrozil, a Lipid-lowering Drug, Increases Myelin Genes in Human Oligodendrocytes via Peroxisome Proliferator-activated Receptor-β

“…For example, PPAR-␣ mRNA was present in primary oligodendrocytes at an undetectable level. This is consistent with a previous report by Granneman et al (4) that also shows the absence of PPAR-␣ in rat and mouse oligodendrocytes (4,35,38). Gemfibrozil was also unable to stimulate the level of PPAR-␣ in oligodendrocytes.…”

Mouse brain plasmalogens are targets for hypochlorous acid-mediated modification in vitro and in vivo

“…This is supported by the fact that glycerol-3-phosphate-O-acyltransferase, a key enzyme in plasmalogen biosynthesis, is significantly down-regulated by TNFα (which was significantly upregulated during this study; Fig. 5) under in vitro and in vivo conditions [64,65]. Activation of a plasmalogen-specific phospholipase could be another factor contributing to plasmalogen loss under inflammatory conditions [41].…”

Protective effects of estradiol on TRAIL-induced apoptosis in a human oligodendrocytic cell line: evidence for multiple sites of interactions

“…These effects may contribute together to generate oligodendrocytes more resistant to different apoptotic stimuli, including TRAIL. Along with the involvement of oligodendrocytes in demyelinating processes, 47,48 and with the protective properties of estrogens in murine EAE, 49,50 our findings suggest novel potential targets for estrogen therapy of MS, and provide further rationale for therapeutic intervention.…”

“…2 Accordingly, although the precise mechanism(s) underlying oligodendrocyte death during MS poussé es has not yet been elucidated, the loss of these cells is one of the major factors for progression of the disease. 3,4 Interestingly, proinflammatory/proapoptotic cytokines, particularly those belonging to the tumour necrosis factor (TNF) superfamily, have been suggested to be, at least in part, responsible for increased cell death rate in the central nervous system (CNS), involving both the neuronal 5 and the glial 6 component. In this line, recent observations suggest that the tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) could play a role in the pathogenesis of MS, as its increased activity is associated with detrimental effects on oligodendrocytes.…”