title: Blocking angiotensin-converting enzyme induces potent regulatory T cells and modulates TH1- and TH17-mediated autoimmunity.
abstract: The renin-angiotensin-aldosterone system (RAAS) is a major regulator of blood pressure. The octapeptide angiotensin II (AII) is proteolytically processed from the decapeptide AI by angiotensin-converting enzyme (ACE), and then acts via angiotensin type 1 and type 2 receptors (AT1R and AT2R). Inhibitors of ACE and antagonists of the AT1R are used in the treatment of hypertension, myocardial infarction, and stroke. We now show that the RAAS also plays a major role in autoimmunity, exemplified by multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Using proteomics, we observed that RAAS is up-regulated in brain lesions of MS. AT1R was induced in myelin-specific CD4+ T cells and monocytes during autoimmune neuroinflammation. Blocking AII production with ACE inhibitors or inhibiting AII signaling with AT1R blockers suppressed autoreactive TH1 and TH17 cells and promoted antigen-specific CD4+FoxP3+ regulatory T cells (Treg cells) with inhibition of the canonical NF-kappaB1 transcription factor complex and activation of the alternative NF-kappaB2 pathway. Treatment with ACE inhibitors induces abundant CD4+FoxP3+ T cells with sufficient potency to reverse paralytic EAE. Modulation of the RAAS with inexpensive, safe pharmaceuticals used by millions worldwide is an attractive therapeutic strategy for application to human autoimmune diseases.
authors.affiliation: Department of Neurology and Neurological Sciences, Beckman Center for Molecular Medicine, Stanford University, Stanford, CA 94305, USA. michael.platten@med.-uni-heidelberg.de
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
authors.forename: Sawsan
authors.initials: S
authors.lastname: Youssef
authors.forename: Eun Mi
authors.initials: EM
authors.lastname: Hur
authors.forename: Peggy P
authors.initials: PP
authors.lastname: Ho
authors.forename: May H
authors.initials: MH
authors.lastname: Han
authors.forename: Tobias V
authors.initials: TV
authors.lastname: Lanz
authors.forename: Lori K
authors.initials: LK
authors.lastname: Phillips
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Goldstein
authors.forename: Roopa
authors.initials: R
authors.lastname: Bhat
authors.forename: Cedric S
authors.initials: CS
authors.lastname: Raine
authors.forename: Raymond A
authors.initials: RA
authors.lastname: Sobel
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D006801:Humans; D020381:Interleukin-17 / Q000276:immunology; D051379:Mice; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D007703:Peptidyl-Dipeptidase A
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