IL-1β-mediated adaptive reprogramming of endogenous human cardiac fibroblasts to cells with immune features during fibrotic remodeling

The source and roles of fibroblasts and T-cells during maladaptive remodeling and myocardial fibrosis in the setting of pulmonary arterial hypertension (PAH) have been long debated. We demonstrate, using single-cell mass cytometry, a subpopulation of endogenous human cardiac fibroblasts expressing increased levels of CD4, a helper T-cell marker, in addition to myofibroblast markers distributed in human fibrotic RV tissue, interstitial and perivascular lesions in SUGEN/Hypoxia (SuHx) rats, and fibroblasts labeled with pdgfr alpha CreERt2/+ in R26R-tdTomato mice. Recombinant IL-1 beta increases IL-1R, CCR2 receptor expression, modifies the secretome, and differentiates cardiac fibroblasts to form CD68-positive cell clusters. IL-1 beta also activates stemness markers, such as NANOG and SOX2, and genes involved in dedifferentiation, lymphoid cell function and metabolic reprogramming. IL-1 beta induction of lineage traced primary mouse cardiac fibroblasts causes these cells to lose their fibroblast identity and acquire an immune phenotype. Our results identify IL-1 beta induced immune-competency in human cardiac fibroblasts and suggest that fibroblast secretome modulation may constitute a therapeutic approach to PAH and other diseases typified by inflammation and fibrotic remodeling. A population of human cardiac fibroblasts displays features of both mesenchymal and lymphoid origin cells and these cells reside in pulmonary arterial hypertension fibrotic tissue of patients and a rat model.

Automated summary

Using single-cell mass cytometry, researchers have identified a subpopulation of human cardiac fibroblasts in fibrotic tissue of pulmonary arterial hypertension patients that display features of both mesenchymal and lymphoid origin cells. Induction of IL-1 beta in these fibroblasts results in immune competency and suggests modulation of fibroblast secretome as a potential therapeutic approach for pulmonary arterial hypertension and other inflammation-related fibrotic diseases.