Inflammatory IL-1 signaling remodels epidermal stem cell compartments by suppressing Wnt activity

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Abstract
The skin epidermis is maintained by spatially organized stem cell populations with distinct cellular dynamics; however, how inflammation affects this heterogeneity remains largely unknown. Here, we demonstrate that acute skin inflammation alters epidermal stem cell compartments through IL-1-mediated suppression of canonical Wnt signaling. Lineage tracing in inflamed mouse skin revealed that slow-cycling Dlx1+ epidermal stem cell clones persist, whereas fast-cycling Slc1a3+ clones decline through enhanced differentiation and lineage conversion, driving the reorganization of epidermal stem cell compartments. IL-1 signaling is both necessary and sufficient for this change: administration of IL-1 recapitulates these effects, while transgenic induction of the IL-1 decoy receptor preserves the balance of stem cell populations. IL-1 suppresses canonical Wnt activity in both the mouse epidermis and human keratinocytes, and Wnt ligand administration restores the fast-cycling compartment in vivo. Together, these results identify a reversible IL-1-Wnt axis that governs inflammation-induced stem cell plasticity and spatial tissue remodeling.
Funding Information
  • Japan Agency for Medical Research and Development (JP25bm1123052)
  • Japan Agency for Medical Research and Development (JP21gm6110016)
  • Japan Society for the Promotion of Science (20H03266)
  • Japan Society for the Promotion of Science (24K02035)
  • Japan Society for the Promotion of Science (22K15126)
  • Lydia O’Leary Memorial Pias Dermatological Foundation

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