Single-cell RNA sequencing reveals dysregulated fibroblast subclusters in prurigo nodularis

作者：Jay R. Patel, Marina Z. Joel, Kevin K. Lee, Anusha Kambala, Hannah Cornman, Olusola O. Oladipo, Matthew T. Taylor, June Deng, Varsha Parthasarathy, Karen Cravero, Melika Marani, Ryan Zhao, Sreenidhi Sankararam, Ruixiang Li, Thomas Pritchard, Vito Rebecca, Madan M. Kwatra, Won Jin Ho, Xinzhong Dong, Sewon Kang, Shawn G. Kwatra · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2023 · DOI：10.1101/2023.01.29.526050 · 被引用次数：10 · 研究领域：Dermatology and Skin Diseases、IL-33, ST2, and ILC Pathways、T-cell and B-cell Immunology

Prurigo nodularis (PN) is an intensely pruritic, chronic inflammatory skin disease that disproportionately affects black patients. However, the pathogenesis of PN is poorly understood. We performed single-cell transcriptomic profiling, ligand receptor analysis and cell trajectory analysis of 28,695 lesional and non-lesional PN skin cells to uncover disease-identifying cell compositions and genetic characteristics. We uncovered a dysregulated role for fibroblasts (FBs) and myofibroblasts as a key pathogenic element in PN, which were significantly increased in PN lesional skin. We defined seven unique subclusters of FBs in PN skin and observed a shift of PN lesional FBs towards a cancer-associated fibroblast (CAF)-like phenotype, with WNT5A+ CAFs increased in the skin of PN patients and similarly so in squamous cell carcinoma (SCC). A multicenter PN cohort study subsequently revealed an increased risk of SCC as well as additional CAF-associated malignancies in PN patients, including breast and colorectal cancers. Systemic fibroproliferative diseases were also upregulated in PN patients, including renal sclerosis and idiopathic pulmonary fibrosis. Ligand receptor analyses demonstrated increased FB1-derived WNT5A and periostin interactions with neuronal receptors MCAM and ITGAV, suggesting a fibroblast-neuronal axis in PN. Type I IFN responses in immune cells and increased angiogenesis/permeability in endothelial cells were also observed. As compared to atopic dermatitis (AD) and...