title: Innate signaling promotes formation of regulatory nitric oxide-producing dendritic cells limiting T-cell expansion in experimental autoimmune myocarditis.
abstract: BACKGROUND
  Activation of innate pattern-recognition receptors promotes CD4+ T-cell-mediated autoimmune myocarditis and subsequent inflammatory cardiomyopathy. Mechanisms that counterregulate exaggerated heart-specific autoimmunity are poorly understood.
  
  
  RESULTS
  Experimental autoimmune myocarditis was induced in BALB/c mice by immunization with α-myosin heavy chain peptide and complete Freund's adjuvant. Together with interferon-γ, heat-killed Mycobacterium tuberculosis, an essential component of complete Freund's adjuvant, converted CD11b(hi)CD11c(-) monocytes into tumor necrosis factor-α- and nitric oxide synthase 2-producing dendritic cells (TipDCs). Heat-killed M. tuberculosis stimulated production of nitric oxide synthase 2 via Toll-like receptor 2-mediated nuclear factor-κB activation. TipDCs limited antigen-specific T-cell expansion through nitric oxide synthase 2-dependent nitric oxide production. Moreover, they promoted nitric oxide synthase 2 production in hematopoietic and stromal cells in a paracrine manner. Consequently, nitric oxide synthase 2 production by both radiosensitive hematopoietic and radioresistant stromal cells prevented exacerbation of autoimmune myocarditis in vivo.
  
  
  CONCLUSIONS
  Innate Toll-like receptor 2 stimulation promotes formation of regulatory TipDCs, which confine autoreactive T-cell responses in experimental autoimmune myocarditis via nitric oxide. Therefore, activation of innate pattern-recognition receptors is critical not only for disease induction but also for counterregulatory mechanisms, protecting the heart from exaggerated autoimmunity.
authors.affiliation: Cardioimmunology, Cardiovascular Research, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. przemyslaw.blyszczuk@uzh.ch
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kania
authors.forename: Stefanie
authors.initials: S
authors.lastname: Siegert
authors.forename: Silvia
authors.initials: S
authors.lastname: Behnke
authors.forename: Rafael
authors.initials: R
authors.lastname: Prados-Rosales
authors.forename: Arturo
authors.initials: A
authors.lastname: Casadevall
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Sanjiv A
authors.initials: SA
authors.lastname: Luther
authors.forename: Manfred
authors.initials: M
authors.lastname: Kopf
authors.forename: Urs
authors.initials: U
authors.lastname: Eriksson
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Blyszczuk
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology / Q000503:physiopathology*; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000276:immunology / Q000517:prevention & control; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D003713:Dendritic Cells / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000528:radiation effects; D007108:Immune Tolerance / Q000276:immunology / Q000502:physiology*; D007371:Interferon-gamma / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D009169:Mycobacterium tuberculosis / Q000276:immunology; D009205:Myocarditis / Q000276:immunology / Q000503:physiopathology*; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis* / Q000235:genetics; D019899:Paracrine Communication; D010446:Peptide Fragments / Q000276:immunology / Q000633:toxicity; D011828:Radiation Chimera; D011836:Radiation Tolerance; D015398:Signal Transduction; D017154:Stromal Cells / Q000201:enzymology / Q000528:radiation effects; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology / Q000473:pathology*; D051195:Toll-Like Receptor 2 / Q000502:physiology*; D024723:Ventricular Myosins / Q000276:immunology / Q000633:toxicity
chemical_list: D016328:NF-kappa B; D010446:Peptide Fragments; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D024723:Ventricular Myosins
keywords: autoimmunity; immunology; myocarditis; nitric oxide