Direct angiotensin type 2 receptor (AT2R) stimulation attenuates T-cell and microglia activation and prevents demyelination in experimental autoimmune encephalomyelitis in mice.

Détails

ID Serval
serval:BIB_03B2EE9FF46E
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Direct angiotensin type 2 receptor (AT2R) stimulation attenuates T-cell and microglia activation and prevents demyelination in experimental autoimmune encephalomyelitis in mice.
Périodique
Clinical Science
Auteur(s)
Valero-Esquitino V., Lucht K., Namsolleck P., Monnet-Tschudi F., Stubbe T., Lucht F., Liu M., Ebner F., Brandt C., Danyel L.A., Villela D.C., Paulis L., Thoene-Reineke C., Dahlöf B., Hallberg A., Unger T., Sumners C., Steckelings U.M.
ISSN
1470-8736 (Electronic)
ISSN-L
0143-5221
Statut éditorial
Publié
Date de publication
2015
Peer-reviewed
Oui
Volume
128
Numéro
2
Pages
95-109
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't Publication Status: ppublish
Résumé
In the present study, we evaluated stimulation of the angiotensin type 2 receptor (AT2R) by the selective non-peptide agonist Compound 21 (C21) as a novel therapeutic concept for the treatment of multiple sclerosis using the model of experimental autoimmune encephalomyelitis (EAE) in mice. C57BL-6 mice were immunized with myelin-oligodendrocyte peptide and treated for 4 weeks with C21 (0.3 mg/kg/day i.p.). Potential effects on myelination, microglia and T-cell composition were estimated by immunostaining and FACS analyses of lumbar spinal cords. The in vivo study was complemented by experiments in aggregating brain cell cultures and microglia in vitro. In the EAE model, treatment with C21 ameliorated microglia activation and decreased the number of total T-cells and CD4+ T-cells in the spinal cord. Fluorescent myelin staining of spinal cords further revealed a significant reduction in EAE-induced demyelinated areas in lumbar spinal cord tissue after AT2R stimulation. C21-treated mice had a significantly better neurological score than vehicle-treated controls. In aggregating brain cell cultures challenged with lipopolysaccharide (LPS) plus interferon-γ (IFNγ), AT2R stimulation prevented demyelination, accelerated re-myelination and reduced the number of microglia. Cytokine synthesis and nitric oxide production by microglia in vitro were significantly reduced after C21 treatment. These results suggest that AT2R stimulation protects the myelin sheaths in autoimmune central nervous system inflammation by inhibiting the T-cell response and microglia activation. Our findings identify the AT2R as a potential new pharmacological target for demyelinating diseases such as multiple sclerosis.
Mots-clé
Animals, Demyelinating Diseases/prevention & control, Encephalomyelitis, Autoimmune, Experimental/drug therapy, Female, Interferon-gamma/pharmacology, Mice, Mice, Inbred C57BL, Microglia/drug effects, Microglia/metabolism, Multiple Sclerosis/drug therapy, Nitric Oxide/metabolism, Rats, Receptor, Angiotensin, Type 2/agonists, Receptor, Angiotensin, Type 2/metabolism, Spinal Cord/drug effects, Spinal Cord/metabolism, T-Lymphocytes/drug effects, T-Lymphocytes/metabolism
Pubmed
Web of science
Création de la notice
19/12/2014 15:13
Dernière modification de la notice
20/08/2019 12:25
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