PPARδ deficient mice develop elevated Th1/Th17 responses and prolonged experimental autoimmune encephalomyelitis.

Neuroscience Research Laboratory, Methodist Research Institute, Indianapolis, IN, USA.
Brain research (Impact Factor: 2.83). 02/2011; 1376:101-12. DOI: 10.1016/j.brainres.2010.12.059
Source: PubMed

ABSTRACT Multiple sclerosis (MS) is a neurological disorder that affects more than a million people worldwide. The etiology of MS is not known and there is no medical treatment that can cure MS. Earlier studies have shown that peroxisome proliferator-activated receptor (PPARs) agonists ameliorate MS-like disease in experimental allergic encephalomyelitis (EAE). In this study we have used PPARδ deficient mice to determine its physiological role in the regulation of CNS EAE and MS. We found that PPARδ(-/-) mice develop EAE with similar day of onset and disease incidence compared to C57BL/6 wild type mice. Interestingly, both male and female PPARδ(-/-) mice showed prolonged EAE with resistance to remission and recovery. PPARδ(-/-) mice with EAE expressed elevated levels of IFNγ and IL-17 along with IL-12p35 and IL-12p40 in the brain and spleen. PPARδ(-/-) mice also developed augmented neural antigen-specific Th1/Th17 responses and impaired Th2/Treg responses compared to wild type mice. These findings indicate that PPARδ(-/-) mice develop prolonged EAE in association with augmented Th1/Th17 responses, suggesting a critical physiological role for PPARδ in the remission and recovery of EAE.

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    ABSTRACT: Multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), results from uncontrolled auto reactive T cells that infiltrate the CNS and attack the myelin sheath. Th17 cells play a prominent role in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Extensive studies have focused on understanding the roles of cytokine signaling and transcriptional network in the differentiation of Th17 cells and their pathogenicity in CNS inflammation. Aside from these events, activated T cells dynamically reprogram their metabolic pathways to fulfill the bioenergic and biosynthetic requirements for proper T cell functions. Emerging evidence indicates that modulation of these metabolic pathways impinges upon the differentiation of Th17 cells and the pathogenesis of EAE. Thus, a better understanding of the functions and mechanisms of T cell metabolism in Th17 cell biology may provide new avenues for therapeutic targeting of MS. In this review, we discuss the recent advances in our understanding of T cell metabolic pathways involved in Th17 cell differentiation and CNS inflammation.
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    ABSTRACT: Background and Objectives. Resistant and susceptible mouse strains to experimental autoimmune encephalomyelitis (EAE), an inducible demyelinating experimental disease serving as animal model for multiple sclerosis, have been described. We aimed to explore MHC-independent mechanisms inducing resistance to EAE. Methods. For EAE induction, female C57BL/6 (susceptible strain) and CD1 (resistant outbred strain showing heterogeneous MHC antigens) mice were immunized with the 35-55 peptide of myelin oligodendrocyte glycoprotein (MOG35-55). We studied T cell proliferation, regulatory and effector cell subpopulations, intracellular and serum cytokine patterns, and titers of anti-MOG serum antibodies. Results. Upon immunization with MOG35-55, T lymphocytes from susceptible mice but not that of resistant strain were capable of proliferating when stimulated with MOG35-55. Accordingly, resistant mice experienced a rise in regulatory B cells (P = 0.001) and, to a lower extent, in regulatory T cells (P = 0.02) compared with C57BL/6 susceptible mice. As a consequence, MOG35-55-immunized C57BL/6 mice showed higher percentages of CD4+ T cells producing both IFN-gamma (P = 0.02) and IL-17 (P = 0.009) and higher serum levels of IL-17 (P = 0.04) than resistant mice. Conclusions. Expansion of regulatory B and T cells contributes to the induction of resistance to EAE by an MHC-independent mechanism.
    Research Journal of Immunology 04/2014; 2014:156380. DOI:10.1155/2014/156380
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    ABSTRACT: Peroxisome proliferator-activated receptors (PPARα, δ, and γ) are ligand-activated transcription factors that regulate a wide range of cellular processes, including inflammation, proliferation, differentiation, metabolism, and energy homeostasis. All three PPAR subtypes have been identified in the central nervous system (CNS) of rodents. While PPARα and PPARγ are expressed in more restricted areas of the CNS, PPARδ is ubiquitously expressed and is the predominant subtype. Although data regarding PPARδ are limited, studies have demonstrated that administration of PPARδ agonists confers neuroprotection following various acute and chronic injuries to the CNS, such as stroke, multiple sclerosis, and Alzheimer's disease. The antioxidant and anti-inflammatory properties of PPARδ agonists are thought to underly their neuroprotective efficacy. This review will focus on the putative neuroprotective benefits of therapeutically targeting PPARδ in the CNS, and specifically, highlight the antioxidant and anti-inflammatory functions of PPARδ agonists.
    PPAR Research 10/2011; 2011:373560. DOI:10.1155/2011/373560 · 1.64 Impact Factor

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