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

Introduction: Psoriasis is a common chronic inflammatory skin disease. Treatments lead to Q6 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. Methods: 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. Results: 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. Discussion: 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.