Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy

G. Christian Baldeviano, Jobert G. Barin, Monica V. Talor, Sachin Srinivasan, Djahida Bedja, Dongfeng Zheng, Kathleen L Gabrielson, Yoichiro Iwakura, Noel R. Rose, Daniela Cihakova

Research output: Contribution to journalArticle

Abstract

RATIONALE: One-third of myocarditis cases progresses to dilated cardiomyopathy (DCM), but the mechanisms controlling this process are largely unknown. CD4+ T helper (Th)17 cells have been implicated in the pathogenesis of autoimmune diseases, but the role of Th17-produced cytokines during inflammation-induced cardiac remodeling has not been previously studied. OBJECTIVE: We examined the importance of interleukin (IL)-17A in the progression of myocarditis to DCM using a mouse model. METHODS AND RESULTS: Immunization of mice with myocarditogenic peptide in complete Freund's adjuvant induced the infiltration of IL-17A-producing Th17 cells into the inflamed heart. Unexpectedly, IL-17A-deficient mice developed myocarditis with similar incidence and severity compared to wild-type mice. Additionally, IL-17A deficiency did not ameliorate the severe myocarditis of interferon (IFN)γ-deficient mice, suggesting that IL-17A plays a minimal role during acute myocarditis. In contrast, IL-17A-deficient mice were protected from postmyocarditis remodeling and did not develop DCM. Flow cytometric and cytokine analysis revealed an important role for IL-17A in heart-specific upregulation of IL-6, TNFα, and IL-1β and the recruitment of CD11b monocyte and Gr1+ granulocyte populations into the heart. Furthermore, IL-17A-deficient mice had reduced interstitial myocardial fibrosis, downregulated expression of matrix metalloproteinase-2 and-9 and decreased gelatinase activity. Treatment of BALB/c mice with anti-IL-17A monoclonal antibody administered after the onset of myocarditis abrogated myocarditis-induced cardiac fibrosis and preserved ventricular function. CONCLUSIONS: Our findings reveal a critical role for IL-17A in postmyocarditis cardiac remodeling and the progression to DCM. Targeting IL-17A may be an attractive therapy for patients with inflammatory dilated cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)1646-1655
Number of pages10
JournalCirculation Research
Volume106
Issue number10
DOIs
StatePublished - May 28 2010

Fingerprint

Interleukin-17
Myocarditis
Dilated Cardiomyopathy
Th17 Cells
Fibrosis
Cytokines
Gelatinases
Ventricular Function
Freund's Adjuvant
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Interleukin-1
Granulocytes
Interferons
Autoimmune Diseases
Monocytes
Immunization
Interleukin-6
Up-Regulation
Down-Regulation

Keywords

  • Autoimmunity
  • Dilated cardiomyopathy
  • IL-17A
  • Myocarditis
  • Th17

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy. / Baldeviano, G. Christian; Barin, Jobert G.; Talor, Monica V.; Srinivasan, Sachin; Bedja, Djahida; Zheng, Dongfeng; Gabrielson, Kathleen L; Iwakura, Yoichiro; Rose, Noel R.; Cihakova, Daniela.

In: Circulation Research, Vol. 106, No. 10, 28.05.2010, p. 1646-1655.

Research output: Contribution to journalArticle

Baldeviano, GC, Barin, JG, Talor, MV, Srinivasan, S, Bedja, D, Zheng, D, Gabrielson, KL, Iwakura, Y, Rose, NR & Cihakova, D 2010, 'Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy', Circulation Research, vol. 106, no. 10, pp. 1646-1655. https://doi.org/10.1161/CIRCRESAHA.109.213157
Baldeviano, G. Christian ; Barin, Jobert G. ; Talor, Monica V. ; Srinivasan, Sachin ; Bedja, Djahida ; Zheng, Dongfeng ; Gabrielson, Kathleen L ; Iwakura, Yoichiro ; Rose, Noel R. ; Cihakova, Daniela. / Interleukin-17A is dispensable for myocarditis but essential for the progression to dilated cardiomyopathy. In: Circulation Research. 2010 ; Vol. 106, No. 10. pp. 1646-1655.
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AU - Baldeviano, G. Christian

AU - Barin, Jobert G.

AU - Talor, Monica V.

AU - Srinivasan, Sachin

AU - Bedja, Djahida

AU - Zheng, Dongfeng

AU - Gabrielson, Kathleen L

AU - Iwakura, Yoichiro

AU - Rose, Noel R.

AU - Cihakova, Daniela

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N2 - RATIONALE: One-third of myocarditis cases progresses to dilated cardiomyopathy (DCM), but the mechanisms controlling this process are largely unknown. CD4+ T helper (Th)17 cells have been implicated in the pathogenesis of autoimmune diseases, but the role of Th17-produced cytokines during inflammation-induced cardiac remodeling has not been previously studied. OBJECTIVE: We examined the importance of interleukin (IL)-17A in the progression of myocarditis to DCM using a mouse model. METHODS AND RESULTS: Immunization of mice with myocarditogenic peptide in complete Freund's adjuvant induced the infiltration of IL-17A-producing Th17 cells into the inflamed heart. Unexpectedly, IL-17A-deficient mice developed myocarditis with similar incidence and severity compared to wild-type mice. Additionally, IL-17A deficiency did not ameliorate the severe myocarditis of interferon (IFN)γ-deficient mice, suggesting that IL-17A plays a minimal role during acute myocarditis. In contrast, IL-17A-deficient mice were protected from postmyocarditis remodeling and did not develop DCM. Flow cytometric and cytokine analysis revealed an important role for IL-17A in heart-specific upregulation of IL-6, TNFα, and IL-1β and the recruitment of CD11b monocyte and Gr1+ granulocyte populations into the heart. Furthermore, IL-17A-deficient mice had reduced interstitial myocardial fibrosis, downregulated expression of matrix metalloproteinase-2 and-9 and decreased gelatinase activity. Treatment of BALB/c mice with anti-IL-17A monoclonal antibody administered after the onset of myocarditis abrogated myocarditis-induced cardiac fibrosis and preserved ventricular function. CONCLUSIONS: Our findings reveal a critical role for IL-17A in postmyocarditis cardiac remodeling and the progression to DCM. Targeting IL-17A may be an attractive therapy for patients with inflammatory dilated cardiomyopathy.

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