Innate signaling promotes formation of regulatory nitric oxide-producing dendritic cells limiting t-cell expansion in experimental autoimmune myocarditis

Gabriela Kania, Stefanie Siegert, Silvia Behnke, Rafael Prados-Rosales, Arturo Casadevall, Thomas F. Lüscher, Sanjiv A. Luther, Manfred Kopf, Urs Eriksson, Przemyslaw Blyszczuk

Research output: Contribution to journalArticle

31 Scopus citations

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. Methods and 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 CD11bhiCD11c- 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.

Original languageEnglish (US)
Pages (from-to)2285-2294
Number of pages10
JournalCirculation
Volume127
Issue number23
DOIs
StatePublished - Jun 11 2013

Keywords

  • Autoimmunity
  • Immunology
  • Myocarditis
  • Nitric oxide

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Kania, G., Siegert, S., Behnke, S., Prados-Rosales, R., Casadevall, A., Lüscher, T. F., Luther, S. A., Kopf, M., Eriksson, U., & Blyszczuk, P. (2013). Innate signaling promotes formation of regulatory nitric oxide-producing dendritic cells limiting t-cell expansion in experimental autoimmune myocarditis. Circulation, 127(23), 2285-2294. https://doi.org/10.1161/CIRCULATIONAHA.112.000434