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Spatial transcriptomic profiling reveals body site-specific inflammatory differences in psoriasis lesions

ABSTRACT: Psoriasis is a common chronic inflammatory skin disease. Treatments lead to substantial improvement of most psoriasis plaques. However, it can be challenging to reach disease resolution in certain hard to treat areas such as scalp, and lower extremity. Here we map histologic and spatial transcriptomic differences between psoriasis lesions across different anatomical locations, to understand if differences can be linked to plaque-site specific treatment resistance. Quantitative immunohistochemical analysis and transcriptomic digital spatial profiling were performed on skin punch biopsies obtained from unaffected areas on the trunk, lesional (LS) areas of the scalp, upper extremity and lower extremity of 12 patients with psoriasis. Histological analysis showed no significant differences in epidermal thickness among LS skin from different body locations. Immunohistochemical markers (CD3, CD4, CD8, CD103, CD207, IL-12RB1, IL-17A, IL-23R, RORγt, FOXP3, and MPO) did not differ significantly between LS sites. Whole transcriptome spatial RNA profiling identified several differentially expressed genes that revealed site-specific transcriptomic differences. Notably, IL-23 signaling was significantly enriched in the lower extremity epidermis, and IL-17 signaling was more pronounced in the epidermis of LS samples. These findings highlight minimal histological and immunohistochemical variation, yet significant transcriptomic and pathway differences between psoriasis body locations, suggesting potential targets for site-specific therapeutic strategies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE310145 | GEO | 2026/03/10

REPOSITORIES: GEO

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Project description:Background: Psoriasis is an inflammatory skin disease associated with systemic inflammation and comorbidities such as diabetes and cardiovascular disease. Although the association between psoriasis and obesity has been studied extensively, the role of cutaneous adipose tissue (CAT) in pathogenesis of psoriasis remains unclear. Objectives This study aimed to provide a comprehensive evaluation of the CAT transcriptome in psoriasis patients and investigate the effects of IL-17 pathway blockade on adipose tissue inflammation. Methods: In this randomized, double-blind, placebo-controlled phase 4 study (ObePso study), CAT biopsies were obtained from lesional (LS-CAT) and non-lesional skin (NL-CAT) of 82 psoriasis patients and 15 healthy controls. Patients were randomized to receive either secukinumab or placebo for 12 weeks. RNA sequencing and subsequent analyses were performed to identify differentially expressed genes and pathways. Results: Psoriatic CAT showed significant gene expression differences compared to controls, with 2132 differentially expressed transcripts identified. Both LS-CAT and NL-CAT exhibited activation of IL-17-induced, antimicrobial peptides-related, and neutrophil degranulation-related pathways. Obesity expanded differential gene expression in psoriasis by more than 100%, suggesting an additive or synergistic interaction between psoriasis and adiposity. Obese psoriasis patients showed activation of pathways related to collagen metabolism, cytokine storm signaling, and IL-17A signaling. Secukinumab treatment significantly improved inflammation in psoriatic CAT, with obese patients showing greater improvement than non-obese patients. Conclusions: This study provides the first comprehensive evaluation of the adipose tissue transcriptome in psoriasis patients. The findings reveal a strong inflammatory signature in psoriatic CAT, which is partly IL-17 dependent. The study also demonstrates that obesity amplifies the inflammatory response in psoriatic adipose tissue. IL-17 blockade with secukinumab significantly improved CAT inflammation, with enhanced benefits observed in obese individuals. These results highlight the potential role of adipose tissue in psoriasis pathogenesis and suggest that targeting adipose tissue inflammation may be a valuable therapeutic approach, particularly in obese psoriasis patients.

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Spatial transcriptomic profiling reveals body site-specific inflammatory differences in psoriasis lesions

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