Genotoxicity induces epithelial hyperplasia and lineage infidelity via fibroblast IL-1β

Epithelial tissues possess a barrier function that must be restored following injury. Repair often involves changes in cell fate, but it remains poorly understood how cell plasticity is induced and whether responses vary with distinct types of damage. Here, we reveal that genotoxic agents, but not mechanical damage, induce hyperplasia and lineage infidelity in the interfollicular epidermis, as well as in two epidermal subappendages: the mammary gland and hair follicle. DNA damage to the epidermis promotes stromal proliferation, and induces basal cell hyperplasia with formation of abnormal, multi-layered K14+/K10+ cells. Unexpectedly, this behavior is epithelial cell non-autonomous, but independent of immunity. Instead, dermal fibroblasts are both necessary and sufficient to induce the epithelial response. We identify a previously unrecognized fibroblast-specific NLRP3 inflammasome that drives this response via IL-1β. Thus, genotoxic agents, used chemotherapeutically to promote cancer cell death, can have the opposite effect on wild-type epithelia, paradoxically promoting hyperplasia and inducing both stemness and lineage infidelity via a non-autonomous, fibroblast-driven mechanism.