Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system.
Angiotensin II is the principle effector molecule of the renin angiotensin system (RAS). It exerts its various actions on the cardiovascular and renal system, mainly via interaction with the angiotensin II type-1 receptor (AT1R), which contributes to blood pressure regulation and development of hypertension but may also mediate effects on the immune system. Here we study the role of the RAS in myelin-oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE), a model mimicking many aspects of multiple sclerosis. Quantitative RT-PCR analyses showed an up-regulation of renin, angiotensin-converting enzyme, as well as AT1R in the inflamed spinal cord and the immune system, including antigen presenting cells (APC). Treatment with the renin inhibitor aliskiren, the angiotensin II converting-enzyme inhibitor enalapril, as well as preventive or therapeutic application of the AT1R antagonist losartan, resulted in a significantly ameliorated course of MOG-EAE. Blockade of AT1R did not directly impact on T-cell responses, but significantly reduced numbers of CD11b+ or CD11c+ APC in immune organs and in the inflamed spinal cord. Additionally, AT1R blockade impaired the expression of CCL2, CCL3, and CXCL10, and reduced CCL2-induced APC migration. Our findings suggest a pivotal role of the RAS in autoimmune inflammation of the central nervous system and identify RAS blockade as a potential new target for multiple sclerosis therapy.
Stegbauer
Johannes
J
Department of Nephrology, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.
Lee
De-Hyung
DH
Seubert
Silvia
S
Ellrichmann
Gisa
G
Manzel
Arndt
A
Kvakan
Heda
H
Muller
Dominik N
DN
Gaupp
Stefanie
S
Rump
Lars Christian
LC
Gold
Ralf
R
Linker
Ralf A
RA
D000577:Amides / Q000627:therapeutic use; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D000938:Antigen-Presenting Cells / Q000166:cytology / Q000276:immunology; D002465:Cell Movement; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000276:immunology; D004656:Enalapril / Q000627:therapeutic use; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D005650:Fumarates / Q000627:therapeutic use; D019808:Losartan / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000276:immunology; D012084:Renin-Angiotensin System / Q000187:drug effects*; D000092502:Renin Inhibitors
D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D018925:Chemokines; D004656:Enalapril; D005650:Fumarates; D019808:Losartan; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D044140:Receptor, Angiotensin, Type 1; D000092502:Renin Inhibitors; C571327:Mog protein, mouse; C446481:aliskiren
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