Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system
Author Affiliations
Department of Nephrology, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany;
Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, D-44791 Bochum, Germany; and
Max-Delbrück-Center for Molecular Medicine and Experimental and Clinical Research Center, Berlin 13125 Berlin, Germany
Published online before print August 19, 2009, doi: 10.1073/pnas.0903602106 PNAS September 1, 2009 vol. 106 no. 35 14942-14947
pnas.org
Abstract
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. |
