Many fibrotic disorders involve immune and inflammatory processes that are promoted by various cytokines, including transforming growth factor β (TGFβ) and IL-13. New findings suggest that Dupuytren disease, a common fibrotic disorder, has immune and inflammatory components that can be inhibited by targeting the JAK–STAT pathway.

Using immunohistochemistry analysis, the researchers identified an enrichment of immune cells in tissue from patients with Dupuytren disease undergoing surgical fasciectomy compared with tissue from patients without Dupuytren disease undergoing hand surgery for carpal tunnel syndrome, including the presence of IL-13-producing mast cells and IFNγ-producing T cells.

To further explore the potential consequences of a cytokine-rich environment, they performed various in vitro experiments on mast cells, fibroblasts from healthy carpal fascia tissue (control fibroblasts) and myofibroblasts from Dupuytren nodules. IFNγ promoted the production of IL-13 by mast cells and, together with TGFβ, increased the expression of the IL-13 receptor IL-13Rα1 by control fibroblasts. Both effects were accompanied by an increase in STAT1 signalling.

IL-13 treatment of control fibroblasts or Dupuytren myofibroblasts promoted cell proliferation, the production of extracellular matrix components (including type I collagen, tenascin C and periostin) and STAT6 signalling. Notably, these effects were greater in the Dupuytren myofibroblasts.

“Differential STAT1 binding at the IL-13Rα1 gene locus drove the enhanced responsiveness of Dupuytren cells to IL-13 compared with control fibroblasts,” explains Neal Millar, corresponding author on the study. “This finding is strongly suggestive of epigenetic modifications.”

Most importantly, a JAK inhibitor (tofacitinib) could decrease STAT signalling in all three cell types and inhibited the fibroproliferative effects of IFNγ and IL-13.