Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 48, Issue 9, Pages 1522-1538Publisher
WILEY
DOI: 10.1002/eji.201847583
Keywords
GM-CSF; Heart failure; IL-17; Fibroblasts; Myocarditis
Categories
Funding
- NIH/NHLBI [R01HL118183, R01HL136586]
- American Heart Association AWRP Winter 2017 [17GRNT33700274]
- Matthew Poyner MVP Memorial Myocarditis Research Fund
- Myocarditis Foundation Postdoctoral Fellowship [90072351]
- American Heart Association Postdoctoral Fellowship [16POST31330012]
- Richard J. and Margaret Conn Himelfarb Student Support Fund
- Johns Hopkins Autoimmune Disease Research Center O'Leary-Wilson Fellowship
- Johns Hopkins Bloomberg School of Public Health Katherine E. Welsh Fellowship
- NIH [R01 HL135657, R01 HL6148315]
- NIH/NIGMS grant [R01GM111682]
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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(+)PDGFR(+)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.
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