title: Role of the renin-angiotensin system in autoimmune inflammation of the central nervous system.
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.
authors.affiliation: Department of Nephrology, Heinrich-Heine-University Düsseldorf, 40225 Düsseldorf, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Stegbauer
authors.forename: De-Hyung
authors.initials: DH
authors.lastname: Lee
authors.forename: Silvia
authors.initials: S
authors.lastname: Seubert
authors.forename: Gisa
authors.initials: G
authors.lastname: Ellrichmann
authors.forename: Arndt
authors.initials: A
authors.lastname: Manzel
authors.forename: Heda
authors.initials: H
authors.lastname: Kvakan
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Muller
authors.forename: Stefanie
authors.initials: S
authors.lastname: Gaupp
authors.forename: Lars Christian
authors.initials: LC
authors.lastname: Rump
authors.forename: Ralf
authors.initials: R
authors.lastname: Gold
authors.forename: Ralf A
authors.initials: RA
authors.lastname: Linker
mesh_terms: 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
chemical_list: 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
references.citation: Immunopharmacol Immunotoxicol. 1995 Aug;17(3):471-91
references.pmid: 8576541
references.citation: Lancet. 1984 Jun 16;1(8390):1325-8
references.pmid: 6145028
references.citation: J Clin Invest. 2009 Apr;119(4):943-53
references.pmid: 19287096
references.citation: FASEB J. 2001 Aug;15(10):1822-4
references.pmid: 11481242
references.citation: Nat Med. 2002 Jun;8(6):620-4
references.pmid: 12042814
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 21;103(47):17985-90
references.pmid: 17090678
references.citation: Clin Res Cardiol. 2008 Jul;97(7):418-31
references.pmid: 18454336
references.citation: Circulation. 2008 Apr 1;117(13):1649-57
references.pmid: 18347211
references.citation: Trends Pharmacol Sci. 2008 Jul;29(7):367-74
references.pmid: 18579222
references.citation: J Mol Med (Berl). 2008 Jun;86(6):659-62
references.pmid: 18443751
references.citation: Annu Rev Pharmacol Toxicol. 1996;36:281-306
references.pmid: 8725391
references.citation: Neurobiol Dis. 2008 May;30(2):162-73
references.pmid: 18342527
references.citation: Arch Neurol. 1997 Aug;54(8):1012-5
references.pmid: 9267976
references.citation: Biochem Biophys Res Commun. 2004 Dec 10;325(2):532-40
references.pmid: 15530425
references.citation: J Immunol. 1998 Jul 1;161(1):430-9
references.pmid: 9647253
references.citation: Am J Pathol. 2002 Nov;161(5):1679-93
references.pmid: 12414515
references.citation: Nat Med. 2009 Jul;15(7):788-93
references.pmid: 19561616
references.citation: N Engl J Med. 1996 Jun 20;334(25):1649-54
references.pmid: 8628362
references.citation: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13854-9
references.pmid: 11698667
references.citation: Exp Nephrol. 1998 Mar-Apr;6(2):112-20
references.pmid: 9567217
references.citation: Nat Med. 2005 Mar;11(3):335-9
references.pmid: 15735651
references.citation: J Exp Med. 2007 Oct 1;204(10):2449-60
references.pmid: 17875676
references.citation: J Immunol. 2008 Feb 15;180(4):2204-13
references.pmid: 18250427
references.citation: Methods. 2001 Dec;25(4):402-8
references.pmid: 11846609
references.citation: J Clin Invest. 2007 Jan;117(1):185-94
references.pmid: 17200718
references.citation: N Engl J Med. 2005 Feb 10;352(6):558-69
references.pmid: 15703421
references.citation: J Clin Invest. 2002 Dec;110(12):1859-68
references.pmid: 12488436
references.citation: J Vasc Res. 2005 Sep-Oct;42(5):399-407
references.pmid: 16088213
references.citation: Invest Ophthalmol Vis Sci. 2009 May;50(5):2255-61
references.pmid: 19136706
references.citation: FASEB J. 2003 Mar;17(3):491-3
references.pmid: 12514109
references.citation: Hypertension. 2005 Jul;46(1):137-43
references.pmid: 15939809
references.citation: J Biol Chem. 1997 Dec 5;272(49):31092-9
references.pmid: 9388261