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: 2.84). 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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    • "PPAR deficient mice had exaggerated EAE symptoms (S.E. Dunn et al., 2010; Kanakasabai et al., 2011) and agonists of PPARγ and PPARα reduced EAE incidence and clinical scores (Diab et al., 2004; Dasgupta et al., 2007). These studies support the experience that immune modulatory functions of endocannabinoids or cannabis are not fully mimicked with Δ 9 -tetrahydrocannabinol (Δ 9 -THC) alone, and exogenous cannabinoids cannot replace a dysfunctional endogenous cannabinoid system. "
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    ABSTRACT: The association between vitamin D and multiple sclerosis has (re)-opened new interest in nutrition and natural compounds in the prevention and treatment of this neuroinflammatory disease. The dietary amount and type of fat, probiotics and biologicals, salmon proteoglycans, phytoestrogens and protease inhibitor of soy, sodium chloride and trace elements, and fat soluble vitamins including D, A and E were all considered as disease-modifying nutraceuticals. Studies in experimental autoimmune encephalomyelitis mice suggest that poly-unsaturated fatty acids and their 'inflammation-resolving' metabolites and the gut microflora may reduce auto-aggressive immune cells and reduce progression or risk of relapse, and infection with whipworm eggs may positively change the gut-brain communication. Encouraged by the recent interest in multiple sclerosis-nutrition nature's pharmacy has been searched for novel compounds with anti-inflammatory, immune-modifying and antioxidative properties, the most interesting being the scorpion toxins that inhibit specific potassium channels of T cells and antioxidative compounds including the green tea flavonoid epigallocatechin-3-gallate, curcumin and the mustard oil glycoside from e.g. broccoli, sulforaphane. They mostly also inhibit pro-inflammatory signaling through NF-κB or toll-like receptors and stabilize the blood brain barrier. Disease modifying functions may also complement analgesic and anti-spastic effects of cannabis, its constituents, and of 'endocannabinoid enhancing' drugs or nutricals like inhibitors of fatty acid amide hydrolase. Nutricals will not solve multiple sclerosis therapeutic challenges but possibly support pharmacological interventions or unearth novel structures. Copyright © 2014. Published by Elsevier Inc.
    Pharmacology [?] Therapeutics 11/2014; 148. DOI:10.1016/j.pharmthera.2014.11.015 · 9.72 Impact Factor
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    • "To further discriminate different T cell responses, we analyzed effector Th1 and Th17 subsets. It has been reported that IL-17 impairs the integrity of the blood brain barrier in EAE [25] and that a rise of spleen Th17 cells prolongs the disease [26]. Moreover, a decrease in IL-17 levels in supernatants of MOG35–55-activated splenocytes runs in parallel with reduced demyelination and axonal damage in mice with EAE [27]. "
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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(5966):156380. DOI:10.1155/2014/156380
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    • "In accord with these findings, PPARδ-null mice with EAE had impaired Th1/Th17 and Th2/Treg responses, which may contribute to the extended recovery time in PPARδ-null mice compared to WT mice. The prolonged EAE in PPARδ-null mice was associated with sustained levels of IFNγ, IL-17, IL-12p35, and IL-12p40, consistent with the hypothesis that PPARδ regulates inflammatory responses associated with EAE [19]. "
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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(2):373560. DOI:10.1155/2011/373560 · 1.64 Impact Factor
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