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

Abstract

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 multi-center 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 psoriasis (PSO) patients, increased mesenchymal dysregulation is unique to PN with an intermediate Th2/Th17 phenotype between atopic dermatitis and psoriasis. These findings identify a pathogenic role for CAFs in PN, including a novel targetable WNT5A+ fibroblast subpopulation and CAF-associated malignancies in PN patients.

Somatic mutations reveal hyperactive Notch signaling and racial disparities in prurigo nodularis

“…Activation of Notch signaling was observed in the lesional skin of patients with systemic sclerosis, and stimulation of healthy dermal fibroblasts with a Notch1 ligand resulted in a phenotype similar to that of systemic sclerosis with increased release of collagen and differentiation of resting fibroblasts into myofibroblasts (68). Interestingly, these findings are aligned with single-cell RNA sequencing studies indicating increased myofibroblasts in PN lesional skin (14).…”

“…Periostin, an extracellular matrix protein released by skin fibroblasts, is found in the dermis of patients with PN at levels that correlate with itch intensity (74). Recent single-cell studies in PN showed significantly increased periostin in lesional skin and supports a fibroblast-neuronal axis in PN regulated by periostin (14).…”

“…The current understanding of PN biology centers around an interplay between cutaneous inflammation, neuronal dysregulation, and altered keratinocyte differentiation and fibroblast signaling (10)(11)(12)(13). Recent transcriptomic studies show characteristic patterns of immune polarization in PN patients, including both Th2/Th17-centered cutaneous immune activation, and cutaneous and systemic Th22-related cytokine upregulation (10,14). Black patients have a greater genetic risk of developing PN and distinct inflammatory signatures are seen in African American PN patients, suggesting the existence of multiple disease endotypes (15)(16)(17).…”

Single-cell analysis of psoriasis resolution reveals an inflammatory fibroblast state targeted by IL-23 blockade

“…5B). A WNT5A+/POSTN+ fibroblast subset has recently been identified in the inflammatory skin disease prurigo nodularis ( 32 ). In affected individuals, these cells were shifted towards a cancer-associated phenotype and showed a prominent activation of type I interferon responses.…”

Besser spät als nie! Klarheit für eine 114 Jahre alte Erkrankung

“…Damit hatte er, wie sich kürzlich herausstellte, Recht, da es sich bei der Prurigo nodularis um eine eigene Entität handelt, für die inzwischen Genotypen und Immunmechanismen beschrieben worden sind [3-7]. So wurde bei der Erkrankung anhand zellulärer und molekularer Untersuchung von Hautbiopsien eine Inflammation mit Th2-Signatur, neurofunktionelle Störungen, vermehrte Angiogenese und mesenchymale Dysregulation beschrieben [5-7]. Insbesondere die Vermehrung von Fibroblasten, Myofibroblasten und die Entstehung von Fibrose unterscheiden die Prurigo nodularis von anderen Dermatosen wie der Psoriasis und der atopischen Dermatitis.…”