Epidermal Dominance of Metabolically Constrained Immune Niches Underpins Immune Activation Signatures and Clinical Severity in Psoriatic Disease

ABSTRACT

Psoriatic disease is characterised by persistent immune activation that is closely linked to tissue context and clinical severity. How immune metabolism is organised within inflamed skin and across systemic immune compartments remains incompletely elucidated. Here, spatial transcriptomics and CITE‐seq datasets were analysed to characterise immune metabolic niche organisation across skin and circulation. Two metabolic constraint axes capturing oxygen redox and nutrient limitation were used to define metabolically constrained and permissive immune niches within leukocyte‐rich tissue regions and circulating immune lineages. Psoriatic lesions exhibited a pronounced shift towards metabolically constrained immune niches that distinguished psoriasis from atopic dermatitis. This imbalance showed strong spatial organisation, with dominance within the epidermis and close alignment with immune activation programmes. Epidermal metabolic organisation scaled with clinical severity and was accompanied by increased immune activation in severely affected tissue, while dermal organisation remained comparatively stable. Extending these observations to circulation, immune metabolic states were further skewed towards constraint in psoriatic patients with joint involvement, consistent with higher systemic inflammatory burden, with prominent effects observed in CD4 T cells. Together, these findings identify immune metabolic niche organisation as a spatially and systemically structured feature of psoriatic disease that links tissue architecture, immune activation and clinical severity.