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

Lei Wu; SuFey 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

doi:10.1084/jem.20132126

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

Lei Wu, SuFey 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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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 language	English
Pages (from-to)	1449-1464
Number of pages	16
Journal	Journal of Experimental Medicine
Volume	211
Issue number	7
DOIs	https://doi.org/10.1084/jem.20132126
Publication status	Published - 30 Jun 2014
Externally published	Yes

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Copyright the Author(s) 2014. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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10.1084/jem.20132126

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@article{8f69b76824344c6daca900dc76139b30,

title = "Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy",

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.",

author = "Lei Wu and SuFey Ong and Talor, \{Monica V.\} and Barin, \{Jobert G.\} and Baldeviano, \{G. Christian\} and Kass, \{David A.\} and Djahida Bedja and Hao Zhang and Asfandyar Sheikh and Margolick, \{Joseph B.\} and Yoichiro Iwakura and Rose, \{Noel R.\} and Daniela {\v C}ih{\'a}kov{\'a}",

note = "Copyright the Author(s) 2014. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2014",

month = jun,

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doi = "10.1084/jem.20132126",

language = "English",

volume = "211",

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TY - JOUR

T1 - Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy

AU - Wu, Lei

AU - Ong, SuFey

AU - Talor, Monica V.

AU - Barin, Jobert G.

AU - Baldeviano, G. Christian

AU - Kass, David A.

AU - Bedja, Djahida

AU - Zhang, Hao

AU - Sheikh, Asfandyar

AU - Margolick, Joseph B.

AU - Iwakura, Yoichiro

AU - Rose, Noel R.

AU - Čiháková, Daniela

N1 - Copyright the Author(s) 2014. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2014/6/30

Y1 - 2014/6/30

N2 - 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.

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.

UR - https://www.scopus.com/pages/publications/84903796044

U2 - 10.1084/jem.20132126

DO - 10.1084/jem.20132126

M3 - Article

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AN - SCOPUS:84903796044

SN - 0022-1007

VL - 211

SP - 1449

EP - 1464

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 7

ER -

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

Abstract

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