IL-6-mediated Th17 differentiation through RORγt is essential for the initiation of experimental autoimmune myocarditis

• Published in: Cardiovascular research 2011-09, Vol.91 (4), p.640-648
• Main Authors: YAMASHITA, Tomomi, IWAKURA, Tomohiko, FUJIMOTO, Minoru, NAKA, Tetsuji, KISHIMOTO, Tadamitsu, NAKAYAMA, Hiroyuki, FUJIO, Yasushi, MATSUI, Kazuki, KAWAGUCHI, Haruyo, OBANA, Masanori, HAYAMA, Akiko, MAEDA, Makiko, IZUMI, Yasukatsu, KOMURO, Issei, OHSUGI, Yoshiyuki
• Format: Article
• Language: English
• Subjects: Animals; Autoimmune Diseases - etiology; Biological and medical sciences; Cardiology. Vascular system; Cell Differentiation; Heart; Interleukin-6 - physiology; Male; Medical sciences; Mice; Mice, Inbred BALB C; Myocarditis - etiology; Myocarditis. Cardiomyopathies; Nuclear Receptor Subfamily 1, Group F, Member 3 - physiology; Receptors, Interleukin-6 - physiology; STAT3 Transcription Factor - physiology; Th17 Cells - cytology
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvr148

Interleukin (IL)-17-producing helper T (Th17) cells have been proposed to participate in the pathogenesis of chronic inflammation, such as autoimmune myocarditis. IL-6 gene ablation confers the resistance to experimental autoimmune myocarditis (EAM). In this study, we have addressed the pathological roles of IL-6 in the regulation of Th17 cells in EAM. To induce EAM, mice were immunized twice with α-myosin heavy chain peptide. Three weeks after the first injection, the cardiac expression of the Th17-specific transcription factor, retinoic acid receptor-related orphan nuclear receptor (ROR γt), was up-regulated. Consistently, Th17 cells were recruited into EAM hearts, as analysed by flow cytometry. Using the mice with enhanced green fluorescence protein (eGFP) gene knocked-in at RORγt locus (RORγt-eGFP mice), we observed Th17 cell infiltration into inflamed lesions. Pre-treatment with IL-6 receptor (IL-6R)-blocking antibody (anti-IL-6R Ab) inhibited EAM induction in terms of disease severity score (3.5 ± 0.8; IgG vs. 0.5 ± 0.8; anti-IL-6R Ab, n = 6, P< 0.01) and suppressed the myocardial expression of IL-17 and RORγt. In contrast, the administration of anti-IL-6R Ab 7 days after the first immunization failed to show the inhibitory effects, suggesting that IL-6 plays important roles in EAM initiation. Finally, by generating RORγt-eGFP homozygous mice, we revealed that RORγt gene ablation conferred the resistance to EAM induction. IL-6-mediated induction of Th17 cells is critical for the onset of EAM, but not for its progression. IL-6/Th17 signalling could be a promising therapeutic target for the prevention of myocardial inflammation.