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Th1 Effector T cells Induce Cardiac Fibroblasts Transition to Myofibroblasts and Contribute to Pressure Overload Induced Cardiac Fibrosis
Author(s) -
Nevers Tania,
Salvador Ane M,
Velazquez Francisco,
Aronovitz Mark,
Blanton Robert,
Alcaide Pilar
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.306.7
Subject(s) - myofibroblast , cardiac fibrosis , pressure overload , fibrosis , extracellular matrix , fibroblast , heart failure , medicine , microbiology and biotechnology , cancer research , chemistry , immunology , pathology , biology , in vitro , biochemistry , cardiac hypertrophy
Cardiac fibrogenesis is a major pathogenic factor that occurs in heart failure (HF) and results in contractile dysfunction and ventricular dilation. It is known that various inflammatory mediators such as T cells and pro‐fibrotic cytokines play an important part in triggering fibrosis in many different organ systems. We recently demonstrated that T cells represent a major subset of heart infiltrating cells in pressure overload induced heart failure, and contribute to cardiac fibrosis and HF progression. In fact, mice deficient in T cells (TCRa −/− mice) or pharmacological depletion of T cells in WT mice resulted in blunted cardiac fibrosis and preserved cardiac function. However the mechanism by which T cells contribute to cardiac fibrosis and the pathogenesis of non‐ischemic HF is still unclear. Thus, we hypothesize that heart infiltrated T cells perpetuate the fibrotic response by regulating the differentiation and activation of extracellular matrix‐producing cardiac myofibroblasts. To test this hypothesis we used in vitro approaches and the thoracic aortic constriction (TAC) mouse model of pressure overload induced heart failure. Co‐culture of various CD4 T cell subsets with cardiac fibroblasts demonstrated that Th1 cells, in contrast to naïve T cells, adhered directly to cardiac fibroblasts and induced fibroblast to myofibroblast transition, enhancing collagen secretion and regulating the synthesis of extracellular matrix proteins shown to be implicated in fibrosis. Supernatants of Th1 cells only slightly induced myofibroblast transition, indicating the requirement of Th1 cells cross‐talk to cardiac fibroblasts to promote fibrosis. Adoptive transfer of Th1 cells into TCRa −/− mice at 48 hours and 2 weeks post TAC surgery resulted in T cell LV infiltration and was sufficient to induce left ventricular fibrosis, and this was not observed after adoptive transfer of naïve T cells in the onset of TAC. Our data suggest that Th1 cells and cardiac fibroblasts reciprocally influence cardiac fibrosis and the pathogenesis of heart failure. These findings provide an attractive tool to counteract the inflammatory/fibrotic process as an alternative option for the treatment of cardiac fibrosis in non ischemic heart failure. Support or Funding Information NIH HL094706 and AHA 13GRNT14560068 (PA), HL6977(RHK )