Publikationsdatenbank

Direct angiotensin type 2 receptor (AT2R) stimulation attenuates T-cell and microglia activation and prevents demyelination in experimental autoimmune encephalomyelitis in mice (2015)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Valero-Esquitino, Verónica

Lucht, Kristin

Namsolleck, Pawel

Monnet-Tschudi, Florianne

Stubbe, Tobias

Lucht, Franziska

Liu, Meng

Ebner, Friederike

Brandt, Christine

Danyel, Leon A

Villela, Daniel C

Paulis, Ludovit

Thoene-Reineke, Christa (WE 11)

Dahlöf, Björn

Hallberg, Anders

Unger, Thomas

Sumners, Colin

Steckelings, U Muscha

Quelle

Clinical science

Bandzählung: 128

Heftzählung: 2

Seiten: 95 – 109

ISSN: 0143-5221

Sprache

Englisch

Verweise

DOI: 10.1042/CS20130601

Pubmed: 25052203

Kontakt

Institut für Tierschutz, Tierverhalten und Versuchstierkunde

Königsweg 67
14163 Berlin
+49 30 838 61146
tierschutz@vetmed.fu-berlin.de

Abstract / Zusammenfassung

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.