Spatial Proteomic Profiling Reveals Increased Levels of Cholesterol Synthesis Proteins in Psoriasis Vulgaris

Psoriasis arises from a combination of genetic and environmental factors, triggering inflammatory circuits involving innate and adaptive immune responses. While the associated histological changes are well described, the changes on the protein level associated with the inflammation and tissue remodeling have only been characterized to a limited extent and with a low degree of spatial information. Therefore, we aimed to to explore skin layer-specific proteomic changes in psoriatic plaques. Using laser-capture microdissection, we divided skin biopsies from patients with psoriasis (N=8) and healthy controls (N=8) into four layers (stratum corneum, inner epidermis, dermis, and subcutis) and analyzed the protein composition of each layer using mass spectrometry. A total of 7,236 proteins were identified and 1,649 proteins were differentially expressed in lesional versus non-lesional inner epidermis. Several of the upregulated proteins related to innate immunity and cholesterol biosynthesis. Stratum corneum showed a more complex protein composition in psoriatic lesions compared to controls, while dermis exhibited upregulation of proteins involved in IL-17 signaling and neutrophil chemotaxis. No differences were detected in subcutis. Our findings highlight the inner epidermis as central to psoriasis pathology, driven by both innate and adaptive immune mechanisms that are potentially enhanced by an increased cholesterol production.