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

27 Citations (Scopus)

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

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Myocarditis
Nitric Oxide Synthase
Dendritic Cells
Nitric Oxide
Pattern Recognition Receptors
Toll-Like Receptor 2
Freund's Adjuvant
Stromal Cells
Autoimmunity
T-Lymphocytes
Mycobacterium tuberculosis
Hot Temperature
Myosin Heavy Chains
Cardiomyopathies
Interferons
Monocytes
Immunization
Tumor Necrosis Factor-alpha
Antigens
Peptides

Keywords

  • Autoimmunity
  • Immunology
  • Myocarditis
  • Nitric oxide

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

Cite this

Innate signaling promotes formation of regulatory nitric oxide-producing dendritic cells limiting t-cell expansion in experimental autoimmune myocarditis. / Kania, Gabriela; Siegert, Stefanie; Behnke, Silvia; Prados-Rosales, Rafael; Casadevall, Arturo; Lüscher, Thomas F.; Luther, Sanjiv A.; Kopf, Manfred; Eriksson, Urs; Blyszczuk, Przemyslaw.

In: Circulation, Vol. 127, No. 23, 11.06.2013, p. 2285-2294.

Research output: Contribution to journalArticle

Kania, G, Siegert, S, Behnke, S, Prados-Rosales, R, Casadevall, A, Lüscher, TF, Luther, SA, 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, vol. 127, no. 23, pp. 2285-2294. https://doi.org/10.1161/CIRCULATIONAHA.112.000434
Kania, Gabriela ; Siegert, Stefanie ; Behnke, Silvia ; Prados-Rosales, Rafael ; Casadevall, Arturo ; Lüscher, Thomas F. ; Luther, Sanjiv A. ; Kopf, Manfred ; Eriksson, Urs ; Blyszczuk, Przemyslaw. / Innate signaling promotes formation of regulatory nitric oxide-producing dendritic cells limiting t-cell expansion in experimental autoimmune myocarditis. In: Circulation. 2013 ; Vol. 127, No. 23. pp. 2285-2294.
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AB - 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.

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