Autophagy is a self-phagocytic and highly evolutionarily conserved intracellular lysosomal catabolic system, which plays a vital role in a variety of trauma models, including skin wound healing (SWH). However, the roles and potential mechanisms of autophagy in SWH are still controversial. We firstly investigated the role of autophagy in SWH-induced wound closure rate, inflammatory response, and histopathology, utilizing an inhibitor of autophagy 3-methyladenine (3-MA) and its agonist rapamycin (RAP). As expected, we found 3-MA treatment remarkably increased the wound closure rate, combated inflammation response, and mitigated histopathological changes, while RAP delivery aggravated SWH-induced pathological damage. To further exploit the underlying mechanism of autophagy regulating inflammation, the specific inhibitors of yes-associated protein (YAP), Verteporfin, and Anti-IL-33 were applied. Herein, treating with 3-MA markedly suppressed the expression of tumor necrosis factor-α (TNF-α), IL-1β, and IL-6, promoted that of IL-10, IL-33, and ST2, while RAP administration reverted SWH-induced the up-regulation of these inflammatory cytokines mentioned above. Importantly, Verteporfin administration not only down-regulated the expression levels of YAP, TNF-α, and IL-6 but also up-regulated that of IL-33 and IL-10. Unexpectedly, 3-MA or RAP retreatment did not have any impact on the changes in IL-33 among these inflammatory indicators. Furthermore, elevated expression of IL-33 promoted wound closure and alleviated the pathological damage, whereas, its antagonist Anti-IL-33 treatment overtly reversed the above-mentioned effects of IL-33. Moreover, 3-MA in combination with anti-IL-33 treatment reversed the role of 3-MA alone in mitigated pathological changes, but they failed to revert the effect of anti-IL-33 alone on worsening pathological damage. In sum, emerging data support the novel contribution of the YAP/IL-33 pathway in autophagy inhibition against SWH-induced pathological damage, and highlight that the autophagy/YAP/IL-33 signal axis is expected to become a new therapeutic target for SWH.

中文翻译：

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自噬抑制促进伤口闭合，部分依赖于皮肤伤口愈合小鼠模型中的 YAP/IL-33 信号

自噬是一种自噬且在进化上高度保守的细胞内溶酶体分解代谢系统，在各种创伤模型中起着至关重要的作用，包括皮肤伤口愈合 (SWH)。然而，自噬在 SWH 中的作用和潜在机制仍存在争议。我们首先利用自噬抑制剂 3-甲基腺嘌呤 (3-MA) 及其激动剂雷帕霉素 (RAP) 研究了自噬在 SWH 诱导的伤口闭合率、炎症反应和组织病理学中的作用。正如预期的那样，我们发现 3-MA 治疗显着提高了伤口闭合率，对抗炎症反应并减轻了组织病理学变化，而 RAP 递送加重了 SWH 引起的病理损伤。为了进一步探索自噬调节炎症的潜在机制，应用了 yes 相关蛋白 (YAP)、Verteporfin 和抗 IL-33 的特异性抑制剂。在此，3-MA 治疗显着抑制肿瘤坏死因子-α (TNF-α)、IL-1β 和 IL-6 的表达，促进 IL-10、IL-33 和 ST2 的表达，而 RAP 给药则逆转SWH 诱导了上述这些炎性细胞因子的上调。重要的是，Verteporfin 给药不仅下调 YAP、TNF-α 和 IL-6 的表达水平，而且上调 IL-33 和 IL-10 的表达水平。出乎意料的是，在这些炎症指标中，3-MA 或 RAP 再治疗对 IL-33 的变化没有任何影响。此外，IL-33 的高表达促进伤口闭合并减轻病理损伤，而其拮抗剂 Anti-IL-33 治疗明显逆转了 IL-33 的上述作用。此外，3-MA 联合抗 IL-33 治疗逆转了单独 3-MA 在减轻病理变化中的作用，但它们未能逆转单独抗 IL-33 对恶化病理损伤的作用。总之，新出现的数据支持 YAP/IL-33 通路在自噬抑制中对 SWH 诱导的病理损伤的新贡献，并强调自噬/YAP/IL-33 信号轴有望成为 SWH 的新治疗靶点.