Experimental Dermatology最新文献

Alopecia areata (AA) is an inflammatory hair loss disorder caused by an immune-mediated attack of the hair follicle (HF) bulb. Active disease is characterised by a peribulbar proinflammatory infiltrate, HF immune privilege collapse and premature catagen induction, yet the underlying drivers of AA remain poorly understood. With comparable autoimmune inflammatory conditions displaying metabolic alterations, we hypothesised that AA is marked by similar pathobiological changes. To investigate this, we utilised an exploratory metabolomics-based discovery liquid chromatography mass spectrometry (LC–MS) approach. This yielded 32 putatively annotated metabolites significantly altered between lesional and nonlesional AA scalp. Notably, 13-HODE, a linoleic acid metabolite linked to vascular function, was decreased, whilst uric acid (UA), a purine degradation metabolite linked to vascular dysfunction, was increased in the lesional scalp. Moreover, serum LC–MS revealed elevated UA in AA compared to controls, which is linked to systemic endothelial dysfunction. CD31+/ICAM-1+ immunofluorescence co-expression analysis revealed elevated vascular inflammation and endothelial cell activation in the AA scalp. We also experimentally provoked the same response in ex vivo human HF culture via UA or fructose (which increases UA) supplementation. Interestingly, the fructose-generating polyol pathway enzymes, AKR1B1 and SORD, are expressed in the HF, with significantly increased AKR1B1 immunoreactivity in lesional AA HFs, suggesting that fructose can be locally generated by the HF and may contribute to elevated UA levels in AA. Together, these metabolic changes point towards UA-linked microvascular dysfunction in AA, inviting exploration of whether strategies to improve endothelial function and regulate UA are effective in managing AA.

Cutaneous squamous cell carcinoma (cSCC) is a common type of skin cancer, predominantly affecting elderly and immunosuppressed patients. Despite recent therapeutic advances, including the introduction of immune checkpoint inhibitors, outcomes for patients with metastatic or recurrent disease remain poor, underscoring the need for new therapeutic approaches and reliable biomarkers to identify patients at high risk of progression. In this context, receptor tyrosine kinase-like orphan receptor 1 (ROR1), previously associated with poor prognosis and targeted therapeutically in other malignancies, has not yet been investigated in cSCC. This study aimed to evaluate ROR1 expression in cSCC and investigate its potential role as a biomarker for tumour aggressiveness. ROR1 expression was analysed via immunofluorescence in a tissue microarray of 360 cSCC samples from a biobank cohort at the University Hospital Cologne. Fluorescence intensity was quantified and correlated with clinicopathologic features and patient outcomes. High ROR1 expression was detected in 42.5% of samples, predominantly localised at tumour invasive fronts. Elevated ROR1 levels were significantly associated with poor tumour differentiation (p < 0.001), lymph node metastasis (p = 0.007), and perineural invasion (p = 0.005). Although higher ROR1 expression correlated with worse progression-free and metastasis-free survival, these differences did not reach statistical significance. In conclusion, this study identifies ROR1 as a novel marker of aggressive cSCC, linked to poor differentiation, lymphatic spread and perineural invasion. ROR1 holds potential both as a prognostic biomarker and as a therapeutic target, encouraging future exploration of ROR1-directed therapies in advanced cSCC.

Real-world data on the long-term effectiveness of dupilumab in moderate-to-severe atopic dermatitis (AD) remains limited, particularly concerning regional disparities in improvement and the outcomes of extended dosing interval regimens. To evaluate the anatomical region-specific responses to dupilumab and the long-term effectiveness under extended dosing-interval regimens. This retrospective cohort study included moderate-to severe AD patients treated with dupilumab. Eczema Area and Severity Index (EASI)-75/90, Numerical Rating Scale (NRS) ≤ 1, and regional EASI reductions were assessed at 6/12/18 months. Patients reaching EASI-75 switched to extended dosing (every 3/4 weeks), with long-term effectiveness and influencing factors evaluated. 108 patients were included. Percentage reductions in EASI scores from baseline at 4, 6 and 12 months were as follows: head/neck: 58.52%, 82.36% and 89.36%; trunk: 77.95%, 85.82% and 94.68%; upper limbs: 77.11%, 86.49% and 95.45%; and lower limbs: 66.34%, 84.03% and 90.34%, respectively. EASI-75/90 and NRS ≤ 1 responses increased over 18 months, reaching 100%/96.97% and 96.97% respectively. No significant differences in effectiveness were observed between the every-three-weeks and every-four-weeks dosing groups. Dupilumab demonstrates sustained, region-specific effectiveness in moderate-to-severe AD, with delayed but progressive improvement in head and neck region(s). Patients achieving EASI-75 with stable disease can safely transition to every-three-weeks or every-four-weeks dosing regimens.

Advancing age is associated with an increasing prevalence of dry skin conditions such as xerosis, asteatotic eczema and atopic dermatitis (AD). Although broad changes in stratum corneum (SC) lipids and AD history have been implicated, age-related alterations in the SC lipidome within at-risk populations remain unclear. We characterised SC structure and lipidomic profiles in 58 adults with dry, eczema-prone skin across a wide age range. Assessments included visual dryness, biophysical properties (TEWL, capacitance, skin-surface-pH), irritant sensitivity, ATR-FTIR spectroscopy and lipidomic analysis through quantification of extracted SC lipids via mass spectrometry. Age correlated significantly with increased dryness (r = 0.46, p ≤ 0.0001) and reduced hydration (r = -0.42, p ≤ 0.0001). Spectroscopy revealed declines in total lipids (p < 0.0026), water (p < 0.0009), lipid esters (p < 0.0001) and carboxylates (p < 0.0004) with age. Among 1385 quantified lipid species, triacylglycerol (TAG) was most abundant; TAG 46:1;0 associated with dryness (r = -0.42, p ≤ 0.0001). Ceramides CER[AH] (p < 0.0001), CER[AP] (p < 0.0001), CER[AdS] (p = 0.042), CER[NP] (p = 0.031) and CER[NdS] (p < 0.0001) all significantly increased with age relative to protein. Notably, CER[NdS] species shifted towards shorter (16ºC) acyl chains (+2.23%, p = 0.01) and away from longer (24ºC) chains (-3.9%, p < 0.0001). The CER[NdS]/CER[NH] ratio correlated with age (r = 0.59, p < 0.0001), dryness (r = 0.36, p = 0.0006), and barrier integrity (r = 0.59, p < 0.0001) (all p ≤ 0.0006). Within an at-risk population, SC lipid levels change as the skin ages. These changes, especially an increase in short acyl chain NdS ceramides, were associated with the decline in skin barrier function and may help explain the increased prevalence of xerosis and the (re)emergence of eczema in later life.

Abnormal activation of keloid fibroblasts (KFs) within a hypoxic microenvironment is a hallmark of keloid pathogenesis. However, the precise molecular mechanisms by which hypoxia drives fibroblast dysfunction remain insufficiently understood. This study aimed to investigate the role of Stanniocalcin 2 (STC2), a hypoxia-responsive glycoprotein, in modulating keloid fibroblast behaviour under hypoxic conditions and to elucidate its upstream and downstream regulatory networks. We found the expression of STC2 was significantly upregulated in keloid tissues and primary KFs, with expression levels positively correlating with clinical severity, as assessed by the Vancouver Scar Scale. Mechanistically, hypoxia induced STC2 expression via hypoxia-inducible factor-1α. Functional assays revealed that STC2 silencing under hypoxia markedly reduced KF proliferation, migration and extracellular matrix remodelling, as evidenced by downregulation of fibrosis-associated markers including collagen I, α-SMA, MMP2 and MMP9. These inhibitory effects were accompanied by attenuation of ERK and AKT signalling pathway activation. Thus, targeting STC2 disrupts pro-fibrotic signalling and may represent a promising therapeutic strategy for the clinical management of keloid scars by modulating the aberrant hypoxic microenvironment.

Skin vascular endothelial cells (VECs) play a crucial role in regulating vascular function, orchestrating local immune responses, and contributing to the progression of immune-mediated inflammatory skin disorders. Despite their importance, the shared and distinct features of VECs across various inflammatory skin conditions remain poorly understood. We analysed single-cell data from 94 skin samples, encompassing healthy individuals and patients with psoriasis, atopic dermatitis, and lupus erythematosus and established a comprehensive VEC atlas spanning multiple inflammatory skin diseases. Our results highlight both common and disease-specific features of VECs, particularly in immune cell activation, angiogenesis, metabolic processes, and intercellular communication. Notably, post-capillary VECs (cluster P) emerged as the most activated subpopulation, exhibiting significant enrichment in pro-inflammatory signalling pathways. Interestingly, cluster P showed distinct pseudotemporal relationships with different VEC clusters across different inflammatory conditions, suggesting disease-specific transcriptional state transitions. Besides, VECs employ both disease-specific ligand-receptor networks to recruit immune cells and remodel stromal niches, alongside conserved mechanisms preserving vascular-immune crosstalk across pathologies. Our study provides a detailed characterisation of VEC pathology in various forms of skin inflammation and offers novel insights into the role of vascular biology in the pathogenesis of skin diseases.