TY - JOUR
T1 - Innate signaling promotes formation of regulatory nitric oxide-producing dendritic cells limiting t-cell expansion in experimental autoimmune myocarditis
AU - Kania, Gabriela
AU - Siegert, Stefanie
AU - Behnke, Silvia
AU - Prados-Rosales, Rafael
AU - Casadevall, Arturo
AU - Lüscher, Thomas F.
AU - Luther, Sanjiv A.
AU - Kopf, Manfred
AU - Eriksson, Urs
AU - Blyszczuk, Przemyslaw
PY - 2013/6/11
Y1 - 2013/6/11
N2 - 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.
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.
KW - Autoimmunity
KW - Immunology
KW - Myocarditis
KW - Nitric oxide
UR - http://www.scopus.com/inward/record.url?scp=84878929232&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84878929232&partnerID=8YFLogxK
U2 - 10.1161/CIRCULATIONAHA.112.000434
DO - 10.1161/CIRCULATIONAHA.112.000434
M3 - Article
C2 - 23671208
AN - SCOPUS:84878929232
SN - 0009-7322
VL - 127
SP - 2285
EP - 2294
JO - Circulation
JF - Circulation
IS - 23
ER -