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

Summary 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-1α/β 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. Highlight Inflammation induces reversible remodeling of epidermal stem cell compartments Distinct epidermal stem cell populations exhibit differential responses to inflammation IL-1 suppresses canonical Wnt signaling, thereby biasing fast-cycling stem cell behavior Reactivation of Wnt signaling restores stem cell population balance under inflammatory conditions Abstract Figure