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

Lei Wu, Su Fey Ong, Monica V. Talor, Jobert G. Barin, G. Christian Baldeviano, David A. Kass, Djahida Bedja, Hao Zhang, Asfandyar Sheikh, Joseph B. Margolick, Yoichiro Iwakura, Noel R. Rose, Daniela Čiháková

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 - Jun 2014

    Fingerprint

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Wu, L., Ong, S. F., Talor, M. V., Barin, J. G., Baldeviano, G. C., Kass, D. A., Bedja, D., Zhang, H., Sheikh, A., Margolick, J. B., Iwakura, Y., Rose, N. R., & Čiháková, D. (2014). Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy. Journal of Experimental Medicine, 211(7), 1449-1464. https://doi.org/10.1084/jem.20132126