Abstract
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.
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Data availability
The raw data generated in this study, including spatial transcriptomics, bulk RNA-seq, and metabolomics sequencing data, have been deposited in the genome sequence archive (GSA) under accession numbers HRA011913, HRA009804, and OMIX010507. The patient-derived spatial transcriptomics data are available under restricted access due to the inclusion of potentially identifiable human genetic and clinical information. Access can be obtained by submitting a request to the corresponding author for non-commercial academic research purposes and is subject to institutional approval and a data use agreement. Responses to access requests are typically provided within 2–4 weeks. Public gene expression microarray and bulk RNA-seq datasets of psoriasis and associated cohort information were obtained from the GEO database under accession numbers GSE67785, GSE26866, GSE11903, GSE51440, GSE14905, GSE85034, GSE6710, GSE41662, GSE117239, GSE30999, GSE69967, GSE106992, GSE41663, GSE136757, GSE67853, GSE34248, GSE54456, GSE79704, GSE53431, GSE83582, and GSE52471. Single-cell RNA-sequencing data were obtained from GEO under accession number GSE173706. Source data are provided with this paper.
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Acknowledgements
This work was supported by the Key Program of National Natural Science Foundation of China (No. U22A20329 to H.L.), Fundamental and Interdisciplinary Disciplines Breakthrough Plan of the Ministry of Education of China (JYB2025XDXM603 to X.C.), the Natural Science Foundation of China for outstanding Young Scholars (No. 82022060 to H.L.), Key Program of National Natural Science Foundation of China (No.82130090 to X.C.), Science Found for Creative Research Groups of the National Natural Science Foundation of China (No. 82221002 to X.C.), National Natural Science Foundation of China (No. 82203931 and No. 82572076 to Y.T., No. 82504290 to J.G.), China Postdoctoral Science Foundation (No. BX20220355 to Y.T., No. 2023M733957 to Y.T., No. BX20250226 to J.G., and No. 2024M763721 to J.G.), The Excellent Youth Project of Hunan Provincial Natural Science Foundation (No. 2024JJ4094 to Y.T.), as well as The Scientific Research Program of FuRong Laboratory (No. 2023SK2095 to H.L., No. 2024PT5104 to Y.Z., 2025PT5010 to Y.T).
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Y.T., J.G., J.S., X.Z., G.Z., X.C. and H.L. developed the concepts and discussed experiments. Y.T. and J.G. performed the experiments and wrote the manuscript. J.S. and G.Z. performed bioinformatics analysis. Y.T., J.G., J.S., X.Z., L.Y., Y.Z., J.Z., C.X., X.X., Y.X. and H.B. analysed and discussed the data. X.Y., G.Z., and Y.Z. verified statistical methods. J.Z., C.X. and X.X. identified clinical samples. P.L. provided the normal foreskin tissues donated by circumcision patients. X.C. and H.L. revised the manuscript and supervised the project.
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Tian, Y., Guo, J., Sun, J. et al. CD73high fibroblasts orchestrate keratinocyte inflammation in the psoriasis-associated epithelial immune microenvironment. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71323-0
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DOI: https://doi.org/10.1038/s41467-026-71323-0
