Single-cell profiling of prurigo nodularis demonstrates immune-stromal crosstalk driving profibrotic responses and reversal with nemolizumab
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE273559 | GEO | 2024/07/31
REPOSITORIES: GEO
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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.
2022-10-31 | GSE210829 | GEO
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.
2022-10-31 | GSE210852 | GEO
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).
2023-07-08 | GSE213849 | GEO
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.
2024-01-22 | GSE233280 | GEO
Project description:Insight into the pathophysiology of inflammatory skin diseases, especially at the proteomic level, is severely hampered by the lack of adequate in situ data. Skin microdialysis samples from patients with atopic dermatitis (AD, n=6), psoriasis vulgaris (PSO, n=7) or prurigo nodularis (PN, n=6), as well as healthy controls (n=7) were subjected to proteomics and multiplex cytokine analysis. Single-cell RNA sequencing of skin biopsy specimens was used to identify the cellular origin of cytokines. Among the top 20 enriched GO annotations, NAD metabolic process, regulation of secretion by cell, and pyruvate metabolic process were elevated in microdialysates from lesional AD skin compared with both nonlesional skin and controls. The top 20 enriched KEGG pathways in these three groups overlapped almost completely. In contrast, nonlesional skin from patients with PSO or PN and control skin showed no overlap with lesional skin in this KEGG pathway analysis. Lesional skin from patients with PSO, but not AD or PN, showed significantly elevated protein levels of IL-22 and MCP-1 compared to nonlesional skin. IL-8 was elevated in lesional vs nonlesional AD and PSO skin, whereas IL-12p40 was higher only in lesional PSO skin. Integrated single-cell RNA-seq data revealed identical cellular sources of these cytokines in AD, PSO and PN. Based on microdialysate, proteomic data of lesional PSO and PN skin, but not lesional AD skin, differed significantly from those of nonlesional skin. IL-8, IL-22, MCP-1 and IL-12p40 might be suitable markers for minimally invasive molecular profiling.
2024-08-22 | PXD050245 | Pride
Project description:Chronic prurigo (CPG) is a neuroinflammatory, fibrotic dermatosis that is defined by the presence of chronic pruritus (itch lasting longer than 6 weeks), scratch-associated pruriginous skin lesions and history of repeated scratching. Patients with CPG experience a significant psychological burden and a notable impairment in their quality of life. Chronic prurigo of nodular type (CNPG; synonym: prurigo nodularis) represents the most common subtype of CPG. As CNPG is representative for all CPG subtypes, we refer in this review to both CNPG and CPG. We provide an overview of the clinical characteristics and assessment of CPG, the burden of disease and the underlying pathophysiology including associated therapeutic targets. The information provided results from a PubMed search for the latest publications and a database search for current clinical trials (ClinicalTrials.gov, EU Clinical Trials Register [European Medicines Agency]; using the following terms or combinations of terms: 'chronic prurigo', 'prurigo', 'prurigo nodularis', 'pathophysiology', 'therapy', 'biologics', 'treatment'). Dupilumab is the first authorized systemic therapy by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) for CNPG to date. Topical and systemic agents that are currently under investigation in clinical randomized, placebo-controlled phase II and III trials such as biologics (e.g., nemolizumab, vixarelimab/KPL-716, barzolvolimab/CDX-0159), small molecules (ruxolitinib cream, povorcitinib/INCB054707, abrocitinib) and the opioid modulator nalbuphine are highlighted. In the last past 15 years, several milestones have been reached regarding the disease understanding of CPG such as first transcriptomic analysis, first terminology, first guideline, and first therapy approval in 2022, which contributed to improved medical care of affected patients. The broad range of identified targets, current case observations and initiated trials offers the possibility of more drug approvals in the near future.
| S-EPMC10796623 | biostudies-literature
Project description:Prurigo nodualris (PN) is a chronic condition with highly pruritic, hyperkeratotic papules or nodules arising in the setting of chronic pruritus. While PN may serve as a phenotypic presentation of several underlying conditions such as atopic dermatitis, chronic kidney disease-related pruritus, and neurological diseases, it represents a distinct clinical entity that may persist despite the removal of the underlying cause, if one is identified. Neuronal proliferation, eosinophils, mast cells, and small-fiber neuropathy play a role in the production of pruritus in PN, although the exact mechanism has not yet been established. Identifying an underlying cause, if present, is essential to prevent recurrence of PN. Due to often present comorbidities, treatment is typically multimodal with utilization of topical and systemic therapies. We performed a PubMed/MEDLINE search for PN and present a review of recent developments in the treatment of PN. Treatment typically relies on the use of topical or intralesional steroids, though more severe or recalcitrant cases often necessitate the use of phototherapy or systemic immunosuppressives. Thalidomide and lenalidomide can both be used in severe cases; however, their toxicity profile makes them less favorable. Opioid receptor antagonists and neurokinin-1 receptor antagonists represent two novel families of therapeutic agents which may effectively treat PN with a lower toxicity profile than thalidomide or lenalidomide.
| S-EPMC6400231 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-10-31 | GSE210854 | GEO
Project description:BackgroundPrurigo nodularis (PN) is a poorly understood, understudied pruritic dermatosis that reduces quality of life.ObjectiveTo characterize the demographics and comorbidities associated with PN.MethodsCross-sectional study of patients 18 years and older who were seen at the Johns Hopkins Health System between December 6, 2012, and December 6, 2017.ResultsOver the past 5 years, 909 patients with PN were seen at Johns Hopkins Health System. African American patients were 3.4 times more likely to have PN than white patients were (odds ratio [OR], 3.4; 95% confidence interval [CI], 2.9-3.9; P < .001). A comparison of the study patients and race-matched controls revealed that PN was significantly associated with a variety of systemic, cardiovascular, and psychiatric comorbidities, including chronic kidney disease, chronic hepatitis C, chronic obstructive pulmonary disease, congestive heart failure, depression, and atopic dermatitis. Black patients with PN were 10.5 times more likely (OR, 10.5; 95% CI, 7.9-13.9; P < .001) to have HIV than were race-matched controls with atopic dermatitis, and 8 times more likely (OR, 8.0; 95% CI, 5.7-11.1; P < .001) to have HIV than were African American patients with psoriasis.LimitationsOur data describe patients seen by 1 hospital system. Our data identify associated conditions and comorbidities but are unable to support a causal relationship.ConclusionPN disproportionately affects African Americans and is associated with several systemic conditions, including HIV, chronic kidney disease, and diabetes.
| S-EPMC6518410 | biostudies-literature
Project description:Despite robust literature associating IL-31 with pruritic inflammatory skin diseases, its influence on cutaneous inflammation and on the interplay between inflammatory and neurosensory pathways remain unmapped. Here, we examined the consequences of disrupting Il31 and its receptor Il31ra in a mouse model of house dust mite (HDM) allergic dermatitis. Il31-deficient mice displayed an increased number and proportion of cutaneous type 2 cytokine-producing CD4 T cells and serum IgE in response to HDM. Single cell RNA-sequencing analysis of skin CD45+ populations from HDM-treated skin revealed that Il4ra+ monocytes and macrophages capable of fueling a feedforward type 2 inflammatory loop were selectively enriched in Il31ra-deficient HDM dermatitis skin. Thus, IL-31 is not strictly a pro-inflammatory cytokine, but rather an immunoregulatory factor that limits the magnitude of type 2 inflammatory responses in skin.
2023-10-26 | GSE236744 | GEO