期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 211, 期 7, 页码 1441-1456出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20132126
关键词
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资金
- National Institutes of Health (NIH)
- Michel Mirowski MD Discovery Foundation
- W.W. Smith Charitable Trust [H1103]
- Children's Cardiomyopathy Foundation
- NIH/NHLBI [R01HL113008, R01HL118183]
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 Phi) cardiac infiltrates. Depletion of Ly6Chi MO/M Phi 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/M Phi in trans toward a more proinflammatory phenotype via CF-derived GM-CSF. Collectively, this IL-17A-fibroblast-GM-CSF-MO/M Phi axis could provide a novel target for the treatment of DCMi and related inflammatory cardiac diseases.
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