In a second recent study, the researchers aimed to further understand mechanisms that differentiate fibrotic and non-fibrotic skin diseases. The team compared single-cell RNA sequencing data from seven different inflammatory skin diseases. Some of the diseases, like atopic dermatitis and psoriasis, were associated with redness and scaling, but not fibrosis. They also analyzed data from patients with fibrotic diseases such as scleroderma, graft-versus-host disease, and lupus.
Their analyses revealed that fibrotic diseases were associated with greater activity of a protein called STAT1 in fibroblasts, the key cell type that’s hyperactivated in fibrotic diseases. To better understand how STAT1 interacts with the EGFR signaling pathway to drive fibrosis, the researchers developed mouse models that lacked STAT1. When the team activated EGFR, they found that mice without STAT1 showed less fibrosis compared to regular animal models.
“If we activate EGFR by inducing injury when there’s no STAT1 present, none of the fibrotic genes are activated,” says Odell.
The researchers conducted further experiments on cultured fibroblasts in vitro which confirmed that STAT1 was required for the onset of fibrosis.
Current therapies for skin diseases include Janus kinases (JAK) inhibitors, which target the JAK-STAT pathway. Previous research shows that the activation of JAKs can trigger activity of STAT proteins like STAT1. While JAK inhibitors can successfully treat skin diseases like atopic dermatitis and psoriasis, they are less effective in mitigating fibrosis.
The current study shows that EGFR signaling can activate STAT1 independent of JAKs, which could explain why JAK inhibitors don’t work as well for fibrotic diseases. This EGFR-STAT1 pathway is a promising new target for potential therapies, the researchers say.