Systemic administration of orexin A ameliorates established experimental autoimmune encephalomyelitis by diminishing neuroinflammation
Autor: | Camille Miel, Yossan-Var Tan, Laurine Becquet, Gaëtan Riou, Mathilde Leclercq, Olivier Boyer, Alain Couvineau, Catalina Abad, Laetitia Jean |
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Přispěvatelé: | Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER), U1149, Centre de recherche sur l'inflamation (CRI), Institut National de la Santé et de la Recherche Médicale (INSERM) |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Central Nervous System Time Factors [SDV]Life Sciences [q-bio] T-Lymphocytes Anti-Inflammatory Agents Neuro-immunomodulation lcsh:RC346-429 Mice 0302 clinical medicine Neuroinflammation Orexin Receptors Orexin A biology EAE General Neuroscience Experimental autoimmune encephalomyelitis 3. Good health Astrogliosis Neurology Spinal Cord [SDV.IMM]Life Sciences [q-bio]/Immunology Cytokines [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Female Encephalomyelitis Autoimmune Experimental Immunology CCL2 Neuroprotection Myelin oligodendrocyte glycoprotein Multiple sclerosis 03 medical and health sciences Cellular and Molecular Neuroscience Orexin-A mental disorders Glial Fibrillary Acidic Protein medicine CXCL10 Animals RNA Messenger lcsh:Neurology. Diseases of the nervous system Cell Proliferation Orexins business.industry Research Myelin Basic Protein medicine.disease Peptide Fragments Mice Inbred C57BL Disease Models Animal Neuropeptide 030104 developmental biology nervous system Immune System biology.protein Myelin-Oligodendrocyte Glycoprotein business 030217 neurology & neurosurgery |
Zdroj: | Journal of Neuroinflammation Journal of Neuroinflammation, BioMed Central, 2019, 16 (1), ⟨10.1186/s12974-019-1447-y⟩ Journal of Neuroinflammation, Vol 16, Iss 1, Pp 1-12 (2019) |
ISSN: | 1742-2094 |
Popis: | Background Orexins (hypocretins, Hcrt) A and B are GPCR-binding hypothalamic neuropeptides known to regulate sleep/wake states and feeding behavior. A few studies have shown that orexin A exhibits anti-inflammatory and neuroprotective properties, suggesting that it might provide therapeutic effects in inflammatory and neurodegenerative diseases like multiple sclerosis (MS). In MS, encephalitogenic Th1 and Th17 cells trigger an inflammatory response in the CNS destroying the myelin sheath. Here, we investigated the effects of peripheral orexin A administration to mice undergoing experimental autoimmune encephalomyelitis (EAE), a widely used model of MS. Methods Mice were subcutaneously immunized with myelin oligodendrocyte glycoprotein peptide (MOG)35–55 in CFA. Mice were treated intraperitoneally for five consecutive days with either PBS or 300 μg of orexin A starting at a moderate EAE score. Molecular, cellular, and histological analysis were performed by real-time PCR, ELISA, flow cytometry, and immunofluorescence. Results Orexin A strongly ameliorated ongoing EAE, limiting the infiltration of pathogenic CD4+ T lymphocytes, and diminishing chemokine (MCP-1/CCL2 and IP-10/CXCL10) and cytokine (IFN-γ (Th1), IL-17 (Th17), TNF-α, IL-10, and TGF-β) expressions in the CNS. Moreover, orexin A treatment was neuroprotective, decreasing demyelination, astrogliosis, and microglial activation. Despite its strong local therapeutic effects, orexin A did not impair peripheral draining lymph node cell proliferation and Th1/Th17 cytokine production in response to MOG35–55 in vitro. Conclusions Peripherally-administered orexin A ameliorated EAE by reducing CNS neuroinflammation. These results suggest that orexins may represent new therapeutic candidates that should be further investigated for MS treatment. Electronic supplementary material The online version of this article (10.1186/s12974-019-1447-y) contains supplementary material, which is available to authorized users. |
Databáze: | OpenAIRE |
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