DNA crosslinking agents are commonly used in cancer chemotherapy; however, responses of normal tissues to these agents have not been widely investigated. We reveal in mouse interfollicular epidermal, mammary and hair follicle epithelia that genotoxicity does not promote apoptosis but paradoxically induces hyperplasia and fate specification defects in quiescent stem cells. DNA damage to skin causes epithelial and dermal hyperplasia, tissue expansion, and proliferation-independent formation of abnormal K14/K10 dual-positive suprabasal cells. Unexpectedly, this behavior is epithelial cell non-autonomous and independent of an intact immune system. Instead, dermal fibroblasts are both necessary and sufficient to induce the epithelial response, which is mediated by activation of a fibroblast-specific NLRP3 inflammasome and subsequent IL-1β production. Thus, genotoxic agents that are used chemotherapeutically to promote cancer cell death can have the opposite effect on wild-type epithelia by inducing, via a non-autonomous IL-1β-driven mechanism, both hyperplasia and stem cell lineage defects.

DNA交联剂常用于癌症化疗；然而，正常组织对这些药物的反应尚未得到广泛研究。我们在小鼠滤泡间表皮、乳腺和毛囊上皮细胞中发现，基因毒性不会促进细胞凋亡，反而会诱导静止干细胞的增生和命运规范缺陷。皮肤 DNA 损伤导致上皮和真皮增生、组织扩张以及异常 K14/K10 双阳性基底上细胞的增殖独立形成。出乎意料的是，这种行为是上皮细胞非自主的并且独立于完整的免疫系统。相反，真皮成纤维细胞对于诱导上皮反应是必要且充分的，该反应是通过成纤维细胞特异性 NLRP3 炎性体的激活和随后的 IL-1β 产生介导的。因此，用于化疗促进癌细胞死亡的基因毒性剂可以通过非自主性 IL-1β 驱动机制诱导增生和干细胞谱系缺陷，从而对野生型上皮细胞产生相反的作用。