LAUSR

Fibrotic diseases are some of the most challenging conditions to treat owing to a lack of effective therapies. Drug development for such conditions is hampered by a lack of suitable animal models and a poor understanding of the early stages of the pathogenic process. A new study is improving this understanding by revealing details of the cellular environment in Dupuytren disease, a fibrotic disease of the hand. “Localized fibrotic conditions such as Dupuytren disease are relatively neglected and yet provide a unique opportunity to study human fibrosis as they can be diagnosed early and there is an abundant supply of human tissue following surgical excision,” explains corresponding author Jagdeep Nanchahal. “Our study provides a detailed singlecell analysis of the immune landscape in Dupuytren disease and identifies a reciprocal pathogenic signalling circuit between stromal and immune cells.” Previous work from this group had revealed that low concentrations of TNF were present in Dupuytren disease nodules and were necessary for the activation of myofibroblasts, which led to ongoing phase II clinical trials of TNF inhibitors for this disease. In their new study, Nanchahal and colleagues combined singlecell RNA analysis with flow cytometry and in vitro functional studies to decipher which cells produce TNF within fibrotic tissue. “We demonstrated that M2 macrophages and mast cells are key cellular sources of TNF that promotes myofibroblast development,” says Nanchahal. “TNF acts via the inducible TNFR2 receptor and stimulates IL-33 secretion by myofibroblasts. In turn, this IL-33 acts as a potent stimulus for TNF production from the immune cells.” Blocking TNFR2 and IL-33 inhibited the expression of F I B R O S I S