1567 Single-cell RNA sequencing reveals unique fibroblast subclusters in prurigo nodularis

Prurigo nodularis (PN) is an intensely pruritic, chronic inflammatory disease that disproportionately affects black patients. However, the pathogenesis is poorly understood. We performed single-cell transcriptomic profiling of 28,695 lesional and non-lesional PN skin cells to uncover cell compositions and genetic profiles. We defined seven subclusters of fibroblasts (FBs) in PN skin and observed a shift of PN lesional FBs towards cancer-associated fibroblast (CAF) phenotypes. Specifically, we found increased WNT5A+ FBs (colocalization coefficient: 0.18 vs 0.023, p<0.05) and myofibroblasts (percent total: 3.7 vs 0.39, p<0.01) in PN patients, and similar results in squamous cell carcinoma (SCC). A multi-center PN cohort study subsequently revealed an increased risk of SCC (HR 1.67, CI 1.55-1.79) and CAF-associated malignancies in PN patients, including breast and colorectal cancers (p<0.0001). Systemic fibroproliferative diseases were also upregulated in PN patients, including renal sclerosis (HR 5.0, CI 3.7-6.88) and idiopathic pulmonary fibrosis (p<0.001). Ligand receptor analyses demonstrated increased FB1-derived WNT5A and periostin interactions with neuronal receptors MCAM and ITGAV, suggesting a fibroblast-neuronal axis. Type I IFN responses in immune cells and angiogenesis in endothelial cells were also increased (p<0.05). As compared to atopic dermatitis and psoriasis patients, increased mesenchymal dysregulation is unique to PN, with an intermediate resident memory Th2/Th17 phenotype between atopic dermatitis and psoriasis. These findings identify a pathogenic role for cancer-like FBs in PN, including a novel targetable WNT5A+ fibroblast subpopulation and CAF-associated malignancies in PN patients.