IL-1A promotes inflammation while safeguarding epithelial basal cell identity and barrier function

BACKGROUND: The ability of barrier epithelia to sense environmental perturbations and initiate local inflammation is essential for progenitor-mediated epithelial repair and restoration of tissue integrity. OBJECTIVE: We characterized human esophageal epithelial progenitor cell heterogeneity and identified molecular mechanisms regulating epithelial regeneration in eosinophilic esophagitis. METHODS: Single-cell RNA sequencing of the adult human esophagus was integrated with spatial characterization of epithelial cell populations and functional analyses using primary human esophageal organoids and air-liquid interface cultures. RESULTS: Using NGFR (nerve growth factor receptor) and P73 (tumor protein 73), we defined a layer of human basal progenitor cells spanning both papillary and interpapillary regions of the human esophageal epithelium. Proliferating basal progenitor cells were enriched within the papillary epithelium, and a subset of papillary basal progenitor cells displayed active YAP (yes-associated protein) signaling, revealing spatially organized heterogeneity within the progenitor compartment. NGFR-positive basal cells exhibited enhanced organoid-forming capacity and suppressed NOTCH signaling to maintain basal identity. During epithelial regeneration, IL-1A was induced in primary human organoids, and an intraepithelial apical-to-basal IL-1A signaling axis was identified in patients with eosinophilic esophagitis. IL-1A activated NF-κB-dependent transcription, promoted basal progenitor expansion, and enhanced epithelial barrier function. Although IL-13 selectively rewired IL-1A-dependent transcriptional and regenerative programs, IL-1A signaling remained active under inflammatory conditions. CONCLUSION: These findings demonstrate that IL-1A coordinates epithelial inflammatory and regenerative responses in the human esophagus. They further show that the outcome of IL-1A signaling is determined by the surrounding inflammatory milieu, providing a framework for understanding epithelial remodeling in eosinophilic esophagitis.