CD73high fibroblasts orchestrate keratinocyte inflammation in the psoriasis-associated epithelial immune microenvironment.

Metabolic dysregulation within the epithelial immune microenvironment (EIME) drives chronic inflammatory skin diseases like psoriasis, but the immune mechanisms and downstream consequences remain unclear. Here we perform in-depth metabolomic analysis showing that nucleotide metabolism is enhanced in psoriatic patients, with elevated adenosine levels closely correlating with disease severity. Single-cell and spatial transcriptomics analyses revealed that adenosine is primarily generated from a population of CD73high fibroblasts in psoriatic skin through enhanced metabolic processes and catalytic capability. Adenosine acts as a mediator between fibroblasts and keratinocytes, causing mitochondrial dysfunction and generating oxidative stress, resulting in the release of pro-inflammatory mediators in keratinocytes via ADORA2B. Deletion of Cd73 in fibroblasts, Adora2b in keratinocytes, or the use of pharmacological inhibitors of the pathways involved, reduces epidermal inflammation in the imiquimod- and IL-23A-induced mouse skin inflammation models. Our study thus identifies the CD73high fibroblast subsets as regulators of epithelial inflammation through metabolic microenvironment interactions with keratinocytes, providing proof of principle for therapeutic strategies targeting fibroblast-keratinocyte crosstalk in inflammatory skin diseases.