Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy

Lei Wu, SuFey F. Ong, Monica V. Talor, Jobert G. Barin, G. Christian Baldeviano, David A Kass, Djahida Bedja, Hao Zhang, Asfandyar Sheikh, Joseph Bernard Margolick, Yoichiro Iwakura, Noel R. Rose, Daniela Cihakova

Research output: Contribution to journalArticle

Abstract

Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in individuals below the age of 40. We recently reported that IL-17A is required for the development of DCMi. We show a novel pathway connecting IL-17A, cardiac fibroblasts (CFs), GM-CSF, and heart-infiltrating myeloid cells with the pathogenesis of DCMi. Il17ra-/- mice were protected from DCMi, and this was associated with significantly diminished neutrophil and Ly6Chi monocyte/macrophage (MO/M φ) cardiac infiltrates. Depletion of Ly6Chi MO/Mφ also protected mice from DCMi. Mechanistically, IL-17A stimulated CFs to produce key chemokines and cytokines that are critical downstream effectors in the recruitment and differentiation of myeloid cells. Moreover, IL-17A directs Ly6Chi MO/Mφ in trans toward a more proinflammatory phenotype via CF-derived GM-CSF. Collectively, this IL-17A- fibroblast-GM-CSF-MO/Mφ axis could provide a novel target for the treatment of DCMi and related inflammatory cardiac diseases.

Original languageEnglish (US)
Pages (from-to)1449-1464
Number of pages16
JournalJournal of Experimental Medicine
Volume211
Issue number7
DOIs
StatePublished - 2014

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Interleukin-17
Dilated Cardiomyopathy
Fibroblasts
Monocytes
Granulocyte-Macrophage Colony-Stimulating Factor
Macrophages
Myeloid Cells
Chemokines
Heart Diseases
Neutrophils
Heart Failure
Cytokines
Phenotype

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy. / Wu, Lei; Ong, SuFey F.; Talor, Monica V.; Barin, Jobert G.; Baldeviano, G. Christian; Kass, David A; Bedja, Djahida; Zhang, Hao; Sheikh, Asfandyar; Margolick, Joseph Bernard; Iwakura, Yoichiro; Rose, Noel R.; Cihakova, Daniela.

In: Journal of Experimental Medicine, Vol. 211, No. 7, 2014, p. 1449-1464.

Research output: Contribution to journalArticle

Wu, L, Ong, SF, Talor, MV, Barin, JG, Baldeviano, GC, Kass, DA, Bedja, D, Zhang, H, Sheikh, A, Margolick, JB, Iwakura, Y, Rose, NR & Cihakova, D 2014, 'Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy', Journal of Experimental Medicine, vol. 211, no. 7, pp. 1449-1464. https://doi.org/10.1084/jem.20132126
Wu, Lei ; Ong, SuFey F. ; Talor, Monica V. ; Barin, Jobert G. ; Baldeviano, G. Christian ; Kass, David A ; Bedja, Djahida ; Zhang, Hao ; Sheikh, Asfandyar ; Margolick, Joseph Bernard ; Iwakura, Yoichiro ; Rose, Noel R. ; Cihakova, Daniela. / Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy. In: Journal of Experimental Medicine. 2014 ; Vol. 211, No. 7. pp. 1449-1464.
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AB - Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in individuals below the age of 40. We recently reported that IL-17A is required for the development of DCMi. We show a novel pathway connecting IL-17A, cardiac fibroblasts (CFs), GM-CSF, and heart-infiltrating myeloid cells with the pathogenesis of DCMi. Il17ra-/- mice were protected from DCMi, and this was associated with significantly diminished neutrophil and Ly6Chi monocyte/macrophage (MO/M φ) cardiac infiltrates. Depletion of Ly6Chi MO/Mφ also protected mice from DCMi. Mechanistically, IL-17A stimulated CFs to produce key chemokines and cytokines that are critical downstream effectors in the recruitment and differentiation of myeloid cells. Moreover, IL-17A directs Ly6Chi MO/Mφ in trans toward a more proinflammatory phenotype via CF-derived GM-CSF. Collectively, this IL-17A- fibroblast-GM-CSF-MO/Mφ axis could provide a novel target for the treatment of DCMi and related inflammatory cardiac diseases.

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