PPARδ deficient mice develop elevated Th1/Th17 responses and prolonged experimental autoimmune encephalomyelitis
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.
- SourceAvailable from: Katja Schmitz
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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. "
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 · 7.75 Impact Factor
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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: An integral part of the Comprehensive Nuclear-Test-Ban Treaty International Monitoring System is an infrasound monitoring network. This network has the capability to detect and verify infrasonic signals-of-interest, e.g., nuclear explosions, from other unwanted infrasound noise sources. The paper presents classification results of infrasonic events using a robust neural networkNeural Networks, 2002. IJCNN '02. Proceedings of the 2002 International Joint Conference on; 02/2002