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Mechanical stretch exacerbates imiquimod-induced dermatitis associated with increased IL-1β and IL-6 production.

ABSTRACT: Psoriasis vulgaris is a chronic inflammatory skin disease which tends to affect the extensor surface of the body. IL-17A and IL-23 antagonists are currently the main and powerful therapeutic choices but the skin areas which are subject to stretching, namely knees, elbows and the lower back, are often reluctant to treatments. ; Hence, we hypothesize that stretching has a dominant effect on psoriasis development. First, we found that, in imiquimod-treated psoriasis-like mouse model, mechanical stretch promotes a significant increase in clinical severity, epidermal thickness, and inflammatory cell infiltration of psoriasis. Transcriptomics profiling revealed that Il6 and Il1b genes are significantly upregulated and play a major role in the activation and recruitment of neutrophils, macrophages, and T cells in stretching group. Upstream analysis further identifies NF-κB as a critical transcription factor to drive pro-inflammatory cytokine expression during stretch application. Immunofluorescence staining confirmed the increased expression of IL-1β and IL-6. In summary, our findings uncover that the mechanical biology contributes to psoriasis progression mainly through enhancing the production of IL-1β and IL-6.

ORGANISM(S): Mus musculus

PROVIDER: GSE218745 | GEO | 2024/07/29

REPOSITORIES: GEO

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Project description:The clinical features of psoriasis, characterized by sharply demarcated scaly erythematous plaques, are typically so distinctive that a diagnosis can easily be made on these grounds alone. However, there is great variability in treatment response between individual patients, and this may reflect heterogeneity of inflammatory networks driving the disease. In this study, whole-genome transcriptional profiling was used to characterize inflammatory and cytokine networks in 62 lesional skin samples obtained from patients with stable chronic plaque psoriasis. We were able to stratify lesions according to their inflammatory gene expression signatures, identifying those associated with strong (37% of patients), moderate (39%) and weak inflammatory infiltrates (24%). Additionally, we identified differences in cytokine signatures with heightened cytokine-response patterns in one sub-group of lesions (IL-13-strong; 50%) and attenuation of these patterns in a second sub-group (IL-13-weak; 50%). These sub-groups correlated with the composition of the inflammatory infiltrate, but were only weakly associated with increased risk allele frequency at some psoriasis susceptibility loci (e.g., REL, TRAF3IP2 and NOS2). Our findings highlight variable points in the inflammatory and cytokine networks known to drive chronic plaque psoriasis. Such heterogeneous aspects may shape clinical course and treatment responses, and can provide avenues for development of personalized treatments. We used Affymetrix microarrays to evaluate genome-wide expression in primary human keratinocytes exposed to cytokines. Cytokine activity signatures were used to interpret the shifts in gene expression that occur in psoriasis plaques relative to normal uninvolved skin. Primary keratinocytes from three donors (subjects 1, 2, and 3) were obtained and were either untreated (control) or exposed to cytokines (IL-4, IL-13, IFN-alpha, IFN-gamma and TNF). For the IL17A samples, primary keratinocytes were obtained from six donors, with cells derived from three donors treated with IL-17A and cells derived from the other three donors left untreated (i.e., unpaired control samples).

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Mechanical stretch exacerbates imiquimod-induced dermatitis associated with increased IL-1β and IL-6 production.

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