Abstract
The causative effect of GM-CSF produced by cardiac fibroblasts to development of heart failure has not been shown. We identified the pathological GM-CSF-producing cardiac fibroblast subset and the specific deletion of IL-17A signaling to these cells attenuated cardiac inflammation and heart failure. We describe here the CD45 − CD31 − CD29 + mEF-SK4 + PDGFRα + Sca-1 + periostin + (Sca-1 + ) cardiac fibroblast subset as the main GM-CSF producer in both experimental autoimmune myocarditis and myocardial infarction mouse models. Specific ablation of IL-17A signaling to Sca-1 + periostin + cardiac fibroblasts (Postn Cre Il17ra fl/fl ) protected mice from post-infarct heart failure and death. Moreover, Postn Cre Il17ra fl/fl mice had significantly fewer GM-CSF-producing Sca-1 + cardiac fibroblasts and inflammatory Ly6C hi monocytes in the heart. Sca-1 + cardiac fibroblasts were not only potent GM-CSF producers, but also exhibited plasticity and switched their cytokine production profiles depending on local microenvironments. Moreover, we also found GM-CSF-positive cardiac fibroblasts in cardiac biopsy samples from heart failure patients of myocarditis or ischemic origin. Thus, this is the first identification of a pathological GM-CSF-producing cardiac fibroblast subset in human and mice hearts with myocarditis and ischemic cardiomyopathy. Sca-1 + cardiac fibroblasts direct the type of immune cells infiltrating the heart during cardiac inflammation and drive the development of heart failure.
Original language | English (US) |
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Pages (from-to) | 1522-1538 |
Number of pages | 17 |
Journal | European Journal of Immunology |
Volume | 48 |
Issue number | 9 |
DOIs | |
State | Published - Sep 2018 |
Keywords
- Fibroblasts
- GM-CSF
- Heart failure
- IL-17
- Myocarditis
ASJC Scopus subject areas
- Immunology and Allergy
- Immunology