Autophagy inhibition facilitates wound closure partially dependent on the YAP/IL-33 signaling in a mouse model of skin wound healing
Autophagy inhibition facilitates wound closure partially dependent on the YAP/IL-33 signaling in a mouse model of skin wound healing
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DOI：
10.1096/fj.202002623rrr
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发表时间：
2021-10-01
期刊：
影响因子：
4.8
通讯作者：
Tao, Luyang
中科院分区：
文献类型：
--
作者：
Gao, Yuan;Luo, Chengliang;Tao, Luyang
自噬是一种高度进化保守的自噬细胞内溶酶体分解代谢系统，在包括皮肤创伤愈合（SWH）在内的多种创伤模型中起着重要作用。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治疗显著增加了伤口闭合率，对抗炎症反应，减轻组织病理学变化，而RAP递送加重了SWH诱导的病理损伤。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（雅普）的特异性抑制剂维替泊芬和抗IL-33。在此，用3-MA处理显著抑制肿瘤坏死因子-α（TNF-α）、IL-1 β和IL-6的表达，促进IL-10、IL-33和ST 2的表达，而RAP施用逆转了上述SWH诱导的这些炎性细胞因子的上调。重要的是，维替泊芬给药不仅下调了雅普、TNF-α和IL-6的表达水平，还上调了IL-33和IL-10的表达水平。出乎意料的是，3-MA或RAP再治疗对这些炎症指标中IL-33的变化没有任何影响。IL-33的高表达可促进伤口愈合，减轻病理损伤，而IL-33拮抗剂可明显逆转IL-33的上述作用。此外，3-MA与抗IL-33治疗的组合逆转了单独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，新出现的数据支持雅普/IL-33通路在自噬抑制SWH诱导的病理损伤中的新贡献，并强调自噬/雅普/IL-33信号轴有望成为SWH的新治疗靶点。
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-alpha (TNF-alpha), IL-1 beta, 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-alpha, 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.