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
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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