Direct angiotensin type 2 receptor (AT 2R) stimulation attenuates T-cell and microglia activation and prevents demyelination in experimental autoimmune encephalomyelitis in mice
| Autor: | Björn Dahlöf, Florianne Monnet-Tschudi, Veronica Valero-Esquitino, Daniel C. Villela, Anders Hallberg, Ludovit Paulis, U. Muscha Steckelings, Thomas Unger, Pawel Namsolleck, Meng Liu, Franziska Lucht, Tobias Stubbe, Christa Thoene-Reineke, Christine Brandt, Kristin Lucht, Colin Sumners, Friederike Ebner, Leon Alexander Danyel |
|---|---|
| Přispěvatelé: | Pathologie, Bedrijfsbureau CD, RS: CARIM - R3 - Vascular biology |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
T-Lymphocytes
experimental autoimmune encephalomyelitis Pharmacology multiple sclerosis neuroinflammation Myelin Mice Neuroinflammation Encephalomyelitis Autoimmune Experimental/drug therapy Microglia/drug effects New therapies Experimental autoimmune encephalomyelitis biology Microglia Chemistry angiotensin type 2 receptor (AT(2)R) General Medicine Receptor Angiotensin Type 2/agonists Neuroprotection medicine.anatomical_structure Spinal Cord neuroprotection Female Encephalomyelitis Autoimmune Experimental Central nervous system Nitric Oxide Demyelinating Diseases/prevention & control Receptor Angiotensin Type 2 Myelin oligodendrocyte glycoprotein Multiple sclerosis Interferon-gamma T-Lymphocytes/drug effects medicine Animals new therapies Angiotensin type 2 receptor (AT R) Spinal Cord/drug effects Interferon-gamma/pharmacology medicine.disease Angiotensin II Oligodendrocyte Rats Mice Inbred C57BL Nitric Oxide/metabolism Immunology biology.protein Multiple Sclerosis/drug therapy Demyelinating Diseases |
| Zdroj: | 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 2015, ' Direct angiotensin type 2 receptor (AT 2 R) stimulation attenuates T-cell and microglia activation and prevents demyelination in experimental autoimmune encephalomyelitis in mice ', Clinical Science, vol. 128, no. 2, pp. 95–109 . https://doi.org/10.1042/CS20130601 Clinical Science, 128(2), 95-109. Portland Press Ltd. |
| ISSN: | 0143-5221 |
| Popis: | 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. Abbreviations: ACE, angiotensin-converting enzyme; AngII, angiotensin II; AT1R, angiotensin type 1 receptor; AT2R, angiotensin type 2 receptor; BBB, blood–brain barrier; BDNF, brain-derived neurotrophic factor; C21, Compound 21; CFA, complete Freund's adjuvant; CNS, central nervous system; DMEM, Dulbecco's modified Eagle's medium; EAE, experimental autoimmune encephalomyelitis; IB-4, isolectin B4; IFN, interferon; IL, interleukin; LPS, lipopolysaccharide; MS, multiple sclerosis; MOG, myelin oligodendrocyte glycoprotein; MOG-EAE, myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis; NF-κB, nuclear factor κB; OPC, oligodendrocyte precursor cell; PFA, paraformaldehyde; p.i., post-immunization; RAS, renin–angiotensin system; TCR, T-cell receptor; TNF, tumour necrosis factor |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|