Irradiation-induced alopecia and dermatitis (IRIAD) are two of the most visually recognized complications of radiotherapy, of which the molecular and cellular basis remains largely unclear. By combining scRNA-seq analysis of whole skin-derived irradiated cells with genetic ablation and molecular inhibition studies, we show that senescence-associated IL-6 and IL-1 signaling, together with IL-17 upregulation and CCR6⁺-mediated immune cell migration, are crucial drivers of IRIAD. Bioinformatics analysis colocalized irradiation-induced IL-6 signaling with senescence pathway upregulation largely within epidermal hair follicles, basal keratinocytes, and dermal fibroblasts. Loss of cytokine signaling by genetic ablation in IL-6^−/− or IL-1R^−/− mice, or by molecular blockade, strongly ameliorated IRIAD, as did deficiency of CCL20/CCR6-mediated immune cell migration in CCR6^−/− mice. Moreover, IL-6 deficiency strongly reduced IL-17, IL-22, CCL20, and CCR6 upregulation, whereas CCR6 deficiency reciprocally diminished IL-6, IL-17, CCL3, and MHC upregulation, suggesting that proximity-dependent cellular cross talk promotes IRIAD. Therapeutically, topical application of Janus kinase blockers or inhibition of T-cell activation by cyclosporine effectively reduced IRIAD, suggesting the potential of targeted approaches for the treatment of dermal side effects in radiotherapy patients.

中文翻译：

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单细胞转录组学揭示了与衰老相关的 IL-6/CCR6 轴驱动放射性皮炎

辐照性脱发和皮炎 (IRIAD) 是两种最直观的放射治疗并发症，其分子和细胞基础仍不清楚。通过将整个皮肤衍生的辐照细胞的 scRNA-seq 分析与基因消融和分子抑制研究相结合，我们发现衰老相关的 IL-6 和 IL-1 信号传导，以及 IL-17 上调和 CCR6 ⁺介导的免疫细胞迁移，是 IRIAD 的关键驱动因素。生物信息学分析主要在表皮毛囊、基底角质形成细胞和真皮成纤维细胞内共定位辐射诱导的 IL-6 信号与衰老通路上调。^{IL-6 -/-}或 IL-1R ^-/-基因消融导致细胞因子信号丢失小鼠或通过分子阻断显着改善了 IRIAD，正如 CCR6 ^-/-小鼠中 CCL20/CCR6 介导的免疫细胞迁移缺陷一样。此外，IL-6 缺乏会强烈降低 IL-17、IL-22、CCL20 和 CCR6 的上调，而 CCR6 缺乏会相互降低 IL-6、IL-17、CCL3 和 MHC 的上调，这表明邻近依赖性细胞串扰促进艾瑞德。在治疗上，Janus 激酶阻滞剂的局部应用或环孢菌素抑制 T 细胞活化可有效降低 IRIAD，这表明靶向方法治疗放射治疗患者皮肤副作用的潜力。