Project description:Prurigo nodularis is a debilitating skin condition that is characterized by chronic itch and a prolonged scratching behavior. Little is known of the underlying molecular mechanisms that initiate and maintain the desease. Therefore, we analyzed DNA methylation in prurigo patients and matched healthy controls.
Project description:Prurigo nodularis is a debilitating skin condition that is characterized by chronic itch and a prolonged scratching behavior. Little is known of the underlying molecular mechanisms that initiate and maintain the desease. Therefore, we analyzed gene expression in prurigo patients and matched healthy controls.
Project description:Prurigo nodularis (PN) is a chronic neuroimmune skin disease characterized by bilaterally distributed pruritic hyperkeratotic nodules on extremities and trunk. Neuroimmune dysregulation and chronic scratching are believed to both induce and maintain the characteristic lesions. This study sought to provide a comprehensive view of the molecular pathogenesis of PN at the single-cell level to identify and outline key pathologic processes and the cell types involved. Features that distinguish PN skin from the skin of patients with atopic dermatitis were of particular interest. We further aimed to determine the impact of the IL31RA antagonist, nemolizumab, and its specificity at the single-cell level.
Project description:Prurigo nodularis (PN) is an intensely pruritic, inflammatory skin disease with a poorly understood pathogenesis. Thus, we performed single-cell transcriptomic profiling of 28,695 lesional and non-lesional PN cells. Lesional PN has increased dysregulated fibroblasts (FBs) and myofibroblasts. FBs in lesional PN were shifted towards a cancer-associated fibroblast (CAF)-like phenotype, with POSTN+WNT5A+ CAFs increased in PN, and similarly so in squamous cell carcinoma. A multi-center cohort study revealed an increased risk of SCC and CAF-associated malignancies (breast and colorectal) in PN patients. Systemic fibroproliferative diseases (renal sclerosis and idiopathic pulmonary fibrosis) were upregulated in PN patients. Ligand receptor analyses demonstrated a fibroblast neuronal axis with FB-derived WNT5A and periostin interactions with neuronal receptors MCAM and ITGAV. Compared to atopic dermatitis and psoriasis, mesenchymal dysregulation is unique to PN with an intermediate Th2/Th17 phenotype. These findings identify a pathogenic and targetable POSTN+WNT5A+ fibroblast subpopulation that may predispose CAF-associated malignancies in PN patients.
Project description:Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized by symmetrically distributed, intensely pruritic nodules of unknown etiology and unmet therapeutic need. The lack of approved therapies and the limited efficacy of off-label treatments reflect the current poor understanding of its pathogenesis. We aimed to comprehensively characterize the phenotypic variation of CD3+ T cells and asses cell-specific gene expression in the lesional skin of patients with PN versus in patients with atopic dermatitis (AD) and in healthy controls (HC). To this end, single-cell RNA sequencing (scRNA-Seq) using 10x Genomics was carried out to compare CD3+ T cells transcriptomic heterogeneity between lesional samples of PN (n=6), AD (n=5) and HC (n=5).
Project description:Prurigo nodularis (PN) is a debilitating neuroimmune skin disease characterized by pruritic, raised, nodular lesions. Psoriasis and AD are classically characterized by Th1/Th17 and Th2 polarization, respectively, but the neuroinflammatory profile of PN remains poorly defined. We characterized the neuroimmune phenotype of PN compared to AD, psoriasis, and healthy controls (HC), through transcriptomic analysis of lesional and nonlesional skin biopsies from 25 PN patients, 27 AD patients, 15 psoriasis patients, and 12 HC using a custom neuroinflammation-focused NanoString panel of 770 genes. Analysis of affected versus unaffected skin revealed differentially expressed genes (DEGs, fold change>1.5, p<0.05) associated with Th1, Th2, and Th17 activation in all three diseases. Upregulated DEGs in PN compared to AD and psoriasis were primarily associated with extracellular matrix remodeling or neural function. Expression of IL-31 was upregulated in PN compared to psoriasis but not AD. Downregulated DEGs in PN compared to AD were associated with Th2 activation and glutamate receptors; those compared to psoriasis were related to Th1 and Th17 activation. PN has a distinct neuroinflammatory signature characterized by intermediate Th1/Th17 and Th2 immune axis activation compared to AD and psoriasis, with increased levels of ECM dysregulation, neuronal abnormalities, and IL-31 activity.
