title: Direct angiotensin type 2 receptor (AT2R) stimulation attenuates T-cell and microglia activation and prevents demyelination in experimental autoimmune encephalomyelitis in mice.
abstract: 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.
authors: *Center for Cardiovascular Research, Charité-Medical Faculty Berlin, Berlin 10115, Germany.
authors: Verónica
authors: V
authors: Valero-Esquitino
authors: *Center for Cardiovascular Research, Charité-Medical Faculty Berlin, Berlin 10115, Germany.
authors: Kristin
authors: K
authors: Lucht
authors: Pawel
authors: P
authors: Namsolleck
authors: ‡Department of Physiology, University of Lausanne, Lausanne CH-1015, Switzerland.
authors: Florianne
authors: F
authors: Monnet-Tschudi
authors: §Center for Anatomy, Institute of Cell Biology and Neurobiology, Charité-Medical Faculty Berlin, Berlin 10115, Germany.
authors: Tobias
authors: T
authors: Stubbe
authors: *Center for Cardiovascular Research, Charité-Medical Faculty Berlin, Berlin 10115, Germany.
authors: Franziska
authors: F
authors: Lucht
authors: ∥Department of Physiology and Functional Genomics, University of Florida Gainesville, FL 32610-0274, U.S.A.
authors: Meng
authors: M
authors: Liu
authors: §Center for Anatomy, Institute of Cell Biology and Neurobiology, Charité-Medical Faculty Berlin, Berlin 10115, Germany.
authors: Friederike
authors: F
authors: Ebner
authors: §Center for Anatomy, Institute of Cell Biology and Neurobiology, Charité-Medical Faculty Berlin, Berlin 10115, Germany.
authors: Christine
authors: C
authors: Brandt
authors: *Center for Cardiovascular Research, Charité-Medical Faculty Berlin, Berlin 10115, Germany.
authors: Leon A
authors: LA
authors: Danyel
authors: ¶Federal University of Minas Gerais (UFMG), Belo Horizonte MG 31270-901, Brazil.
authors: Daniel C
authors: DC
authors: Villela
authors: **Institute of Pathophysiology, Faculty of Medicine, Comenius University, Bratislava 811 08, Slovak Republic.
authors: Ludovit
authors: L
authors: Paulis
authors: ††FEM, Charité-Medical Faculty Berlin, Berlin 10115, Germany.
authors: Christa
authors: C
authors: Thoene-Reineke
authors: ‡‡Sahlgrenska University Hospital/Östra, Göteborg 413 45, Sweden.
authors: Björn
authors: B
authors: Dahlöf
authors: §§Department of Medical Chemistry, Uppsala University, Uppsala 751 23, Sweden.
authors: Anders
authors: A
authors: Hallberg
authors: †CARIM, Maastricht University, Maastricht 6200, The Netherlands.
authors: Thomas
authors: T
authors: Unger
authors: ∥Department of Physiology and Functional Genomics, University of Florida Gainesville, FL 32610-0274, U.S.A.
authors: Colin
authors: C
authors: Sumners
authors: U Muscha
authors: UM
authors: Steckelings
mesh_terms: D000818:Animals; D003711:Demyelinating Diseases / Q000517:prevention & control*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy*; D005260:Female; D007371:Interferon-gamma / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy*; D009569:Nitric Oxide / Q000378:metabolism; D051381:Rats; D044139:Receptor, Angiotensin, Type 2 / Q000819:agonists* / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
chemical_list: D044139:Receptor, Angiotensin, Type 2; D009569:Nitric Oxide; D007371:Interferon-gamma