TGF-β drives myofibroblast activation and inflammatory mediator production in vulvar lichen sclerosus

Abstract

Objective

Vulvar lichen sclerosus (VLS) is a chronic inflammatory skin condition characterized by whitening of the external genitalia, debilitating pruritus (itching), and pain. As disease advances, loss of labia, burying of vulvar anatomy (ie, clitoris, urethra, vaginal opening), and vulvar cancer can occur, yet mechanistic understanding of these events remains limited. VLS lesions appear visibly similar to scars and are frequently referred to as such. Therefore, we investigated the role of fibrosis in the VLS disease mechanism with the goal of identifying targets for new therapeutic and diagnostic strategies.

Study design

6-mm biopsies were collected from 8 participants with VLS from regions of the vulva visibly affected by lichen sclerosus (“scarred”) and adjacent unaffected areas (“unscarred”), allowing each patient to serve as their own control thus diminishing biological noise. Specimens were also used to establish fibroblast strains, and cells were stimulated with TGF-β to assess fibroblast-to-myofibroblast transitions, extracellular matrix (ECM) production, and inflammatory responses in scarred versus unscarred areas.

Results

Fibroblasts from scarred areas expressed higher levels of cytoskeletal proteins (alpha-smooth muscle actin) and inflammatory mediators (interleukin 6, prostaglandin E2) upon TGF-β stimulation compared to their unscarred counterparts. Treatment with SB-431542, a TGF-β receptor inhibitor, quelled these responses (P≤.05), indicating that these effects are mediated through the TGF-β pathway. Fibroblasts isolated from scarred tissues exhibit myofibroblast morphologies, but so do fibroblasts from unscarred areas.

Conclusion

TGF-β activates myofibroblasts and exacerbates inflammation in VLS cells from scarred areas. However, fibroblasts from both scarred and unscarred areas show similarities in morphology and ECM production, suggesting molecular changes may occur in VLS skin before visible changes are detected, which could lead to new diagnostic strategies to treat disease before irreversible architectural changes occur.