Abstract 16932: Local Production of Interleukin-33 and its Ability to Activate Mast Cells to Produce Pro-fibrotic Mediators May be Associated With Cardiac Fibrosis

IntroductionCardiac fibrosis is a complex process in which inflammation is a key component. Mast cells are innate immune sentinel cells found in multiple tissues, including the heart and often associated with a TH2 driven inflammatory response, which promotes fibrosis. After myocardial injury, fibroblast derived interleukin(IL)-33 is thought to be cardioprotective, however it is also known to activate mast cells to a pro-fibrotic phenotype in other disease settings. We hypothesized that mast cells activated with IL-33 would produce mediators known to promote fibrosis.MethodsCardiac mast cells were identified using human atrial tissue (n=35) and blood samples obtained from patients undergoing open-heart surgery. Samples were processed for histological staining and analysis of mediator content. Human cord blood-derived mast cells (CBMCs) were activated in vitro with IL-33 and gene expression of inflammatory markers was assessed, in addition to evaluation of protein production of selected mediators.ResultsHistological staining using toluidine blue confirmed the presence of mast cells in human atrial tissue and associated atrial fibrosis with Sirius red fast green post MI. Human atrial tissue homogenates were found to contain substantial amounts of IL-33 (423.6 ± 41.02 pg/mL, n = 21) in addition to the pro-fibrotic mediators produced by mast cells following IL-33 activation. In vitro assays showed that CBMCs, activated with IL-33, increased production of TH2-associated mediators such as IL-13 and IL-5 (250.4 ± 20.5 pg/mL P < 0.001, and 914.9 ± 246.6 pg/mL P < 0.01, n=5), in addition to the production of pro-fibrotic mediators (VEGF = 61.3 ± 4.0 pg/mL P < 0.001, GM-CSF = 1718.3 ± 268.4 pg/mL P < 0.001, n=5).ConclusionsHuman mast cells activated with IL-33 respond by producing mediators known to promote fibrosis. Given that mast cells and IL-33 are both present in human heart tissue with evidence of ongoing fibrosis, mast cell activation by IL-33 may promote cardiac fibrosis.