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

Background: Chronic nodular prurigo (CNPG) is an inflammatory skin disease that is maintained by a chronic itch -scratch cycle likely rooted in neuroimmunological 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.Objectives: This study aimed to improve the understanding of pathomechanisms underlying CNPG as well as molecular relationships between CNPG and atopic dermatitis (AD).Methods: We profiled skin lesions from patients with CNPG in comparison with AD and healthy control 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 CXCL142IL241 secretory papillary fibroblasts. Besides known itch mediators such as IL31 and oncostatin M, we also detected increased levels of neuromedin B in fibroblasts of CNPG lesions compared with AD and HC, with neuromedin B receptors detectable on some nerve endings.Conclusions: 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 have a direct impact on itch fibers. (J Allergy Clin Immunol 2023;152:420-35.)

Automated summary

This study used single-cell RNA sequencing combined with T-cell receptor sequencing to compare skin lesions from patients with chronic nodular prurigo (CNPG), atopic dermatitis (AD), and healthy individuals. The results showed that both CNPG and AD exhibited type 2 immune skewing, but only AD had an additional population of CD8A+IL9R+IL13+ cytotoxic T-cells and highly upregulated immune activation pathways. In contrast, CNPG showed characteristics of stromal remodeling and fibrosis. These findings contribute to a better understanding of the pathomechanisms and molecular relationships between CNPG and AD.