Prurigo nodularis (PN) is a chronic inflammatory disease characterized by chronic pruritus, pruriginous lesions and history or signs of scratching. Although the pathophysiology of PN is not fully understood, histological analysis of PN nodules reveals epidermal dysregulation (hyperorthokeratosis and hyperplasia), dermal fibrosis and inflammatory cell infiltrate. Present work investigates the role of fibroblasts in PN pathogenesis and the mechanism of action of nemolizumab, an investigational monoclonal antibody that blocks interleukin 31 receptor (IL-31RA).
Here, we combined single-cell and bulk RNA sequencing (RNAseq) to delineate molecular and cellular signatures of PN and investigate the impact of nemolizumab in treated patients. Single-cell RNAseq (scRNAseq) was performed on skin biopsies obtained from 4 patients with PN and 4 healthy controls. The role of fibroblasts in PN pathogenesis was further investigated via a cell-cell communication analysis using CellChat. Bulk RNAseq was performed on skin biopsies obtained at baseline and week 12 from a nemolizumab phase 2 study in patients with PN (n=70, NCT03181503).
scRNAseq results show that compared to healthy skin, lesional PN fibroblasts take on a pro-fibrotic and pro-inflammatory state, confirmed by trajectory analyses, reflecting altered differentiation of fibroblasts in PN skin. Consistent with this, functional analysis of differentially expressed genes in lesional PN fibroblasts indicates activation of inflammatory (TNF, IL1B, IL6) and pro-fibrotic (TGFB) signaling pathways. CellChat results highlight the role of the PN fibroblast as a central player in the intra-cellular cross-talk. Combining bulk and single-cell RNAseq data, we observed that nemolizumab restores neural dysregulation and reduces inflammation and fibrosis.
The current study demonstrates that PN is an inflammatory and fibrotic disease and that nemolizumab exerts an antifibrotic effect via inhibiting critical signaling pathways.

LB058 - Role of fibroblasts in prurigo nodularis pathogenesis and nemolizumab mechanism of action

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.