Single-cell RNA sequencing defines disease-specific differences between chronic nodular prurigo and atopic dermatitis. Single-cell RNA sequencing defines disease-specific differences between chronic nodular prurigo and atopic dermatitis

Background: Chronic nodular prurigo (CNPG) is a chronic inflammatory skin disease that is maintained by a chronic itch-scratch cycle likely rooted in neuro-immunological dysregulation. This condition may be associated with atopy in some patients, and there are now promising therapeutic results from blocking type-2 cytokines such as IL-4, IL-13 and IL-31. Nevertheless, underlying pathomechanisms as well as the molecular relationship with atopy remain ill-defined. Methods: We profiled skin lesions from patients with CNPG in comparison to atopic dermatitis (AD) and healthy control (HC) individuals using single-cell RNA sequencing combined with T-cell receptor sequencing. Results: We found type-2 immune skewing in both CNPG and AD, as evidenced by CD4+ helper T cells expressing IL13. However, only AD harbored an additional, oligoclonally expanded CD8A+ IL9R+ IL13+ cytotoxic T cell population, and immune activation pathways were highly upregulated in AD, but less so in CNPG. Conversely, CNPG showed signatures of extracellular matrix organization, collagen synthesis, and fibrosis, including a unique population of CXCL14- IL24+ secretory-papillary fibroblasts. Besides known itch mediators such as IL31 and oncostatin M (OSM), we also detected increased levels of neuromedin B (NMB) in fibroblasts of CNPG lesions compared to AD and HC, with NMB receptors detectable on some nerve endings. Conclusion: These data show that CNPG does not harbor the strong disease-specific immune activation pathways that are typically found in AD, but is rather characterized by upregulated stromal remodeling mechanisms that might directly impact itch fibers. Overall design: Comparison of skin cells obtained from PN, AD and HC donors. Raw data is not provided due to patient privacy concerns. Healthy Control samples 112 – HC1, 115 – HC2, 116 – HC3 and 121 – HC4 used in this manuscript are already publicly available via Gene Expression Omnibus GSE173205.