Spatial transcriptomics stratifies health and psoriatic disease severity by emergent cellular ecosystems

While human inflammatory skin diseases' cellular and molecular features are well-characterized, their tissue context and systemic impact remain poorly understood. We thus profiled human psoriasis (PsO) as a prototypic immune-mediated condition with a high preference for extra-cutaneous involvement. Spatial transcriptomics (ST) analyses of 25 healthy, active, and clinically uninvolved skin biopsies, and integration with public single-cell transcriptomics data revealed striking differences in immune microniches between healthy and inflamed skin. Tissue scale-cartography further identified core disease features across all active lesions, including the emergence of an inflamed suprabasal epidermal state and the presence of B lymphocytes in lesional skin. Notably, both lesional and distal non-lesional samples were stratified by skin disease severity, and not by the presence of systemic disease. This segregation was driven by macrophage-, fibroblast- and lymphatic-enriched spatial regions with gene signatures associated with metabolic dysfunction. Taken together, these findings suggest that mild and severe forms of PsO have distinct molecular features and that severe PsO may profoundly alter the cellular and metabolic make up of distal unaffected skin sites. Additionally, our study provides an unprecedented resource for the research community to study spatial gene organization of healthy and inflamed human skin.