Immune–stromal dysregulation and senescence in chronic spontaneous urticaria

Background Chronic spontaneous urticaria (CSU) involves mast cells and multiple immune pathways, yet mechanisms sustaining disease chronicity remain incompletely defined.Objective We sought to delineate immune, stromal, and senescence-associated transcriptional programs in CSU lesional skin.Methods Lesional biopsy samples from 28 adults with CSU and 22 matched healthy controls were analyzed by bulk RNA sequencing, guided topic model-based deconvolution, and p16INK4a immunohistochemistry. Differential expression, gene set enrichment, and immune module scoring were performed.Results CSU skin showed 449 differentially expressed genes (309 up, 140 down), including IL4R, LAG3, CXCL8, CASP5, and NLRP12 upregulation, with downregulation of vascular/mesenchymal (CAV1, CD34) and circadian regulators (PER1, NR1D1). Deconvolution revealed expansion of helper, cytotoxic, and regulatory T cells, macrophages, and granulocyte modules, with TH2/TH17 polarization. Fibroblasts, keratinocytes, and melanocytes displayed proinflammatory, remodeling-competent states. Senescence-associated transcripts were enriched, and p16INK4a staining confirmed higher senescent cell density in CSU dermis and hypodermis (median, 92.1 vs 36.0 cells/mm2; P = .014).Conclusions Adult CSU lesions comprise a chronically inflamed immune-stromal niche, integrating T-cell activation, structural cell reprogramming, and cellular senescence. These data extend current models of CSU and identify senescence as a potential amplifier of inflammation and a testable target for future mechanistic and interventional studies.