Cell-surface translocation of annexin A2 contributes to bleomycin-induced pulmonary fibrosis by mediating inflammatory response in mice
Cell-surface translocation of annexin A2 contributes to bleomycin-induced pulmonary fibrosis by mediating inflammatory response in mice
复制标题
膜联蛋白 A2 的细胞表面易位通过介导小鼠炎症反应导致博莱霉素诱导的肺纤维化
DOI：
10.1042/cs20180687
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发表时间：
2019-04-15
期刊：
影响因子：
6
通讯作者：
Zhang, Tao
中科院分区：
文献类型：
--
作者：
Lei, Yunlong;Wang, Kui;Zhang, Tao
博来霉素是一种广泛使用的抗癌药物，可能会引起肺纤维化，这是一种严重的副作用，与显着的发病率和死亡率相关。尽管付出了巨大的努力，肺纤维化的确切发病机制仍有待阐明。我们之前的研究表明，博莱霉素直接与膜联蛋白 A2（ANXA2 或 p36）结合，通过阻碍转录因子 EB (TFEB) 诱导的自噬流而导致肺纤维化的发展。在这里，我们证明 ANXA2 在博莱霉素诱导的炎症中也发挥着关键作用，这是博莱霉素诱导的肺纤维化的另一个主要原因。我们发现博莱霉素可以通过外泌体分泌诱导肺上皮细胞中 ANXA2 的细胞表面易位，这与 ANXA2 和 p11 之间相互作用的增强有关。敲低 ANXA2 或阻断膜 ANXA2 可减轻博莱霉素诱导的核因子 (NF)-κ B 通路激活以及肺上皮细胞中促炎细胞因子 1L-6 的产生。与博莱霉素攻击的野生型小鼠相比，ANXA2 缺陷型 (ANXA2(-/-) ) 小鼠用博来霉素治疗后，肺纤维化减少，细胞因子产生减少。此外，表面 ANXA2 抑制剂 TM601 可以改善博来霉素治疗小鼠的纤维化和炎症反应。综上所述，我们的结果表明，除了干扰自噬流外，ANXA2 还可以通过介导炎症反应来促进博来霉素诱导的肺纤维化。
Bleomycin, a widely used anti-cancer drug, may give rise to pulmonary fibrosis, a serious side effect which is associated with significant morbidity and mortality. Despite the intensive efforts, the precise pathogenic mechanisms of pulmonary fibrosis still remain to be clarified. Our previous study showed that bleomycin bound directly to annexin A2 (ANXA2, or p36), leading to development of pulmonary fibrosis by impeding transcription factor EB (TFEB)-induced autophagic flux. Here, we demonstrated that ANXA2 also played a critical role in bleomycin-induced inflammation, which represents another major cause of bleomycin-induced pulmonary fibrosis. We found that bleomycin could induce the cell surface translocation of ANXA2 in lung epithelial cells through exosomal secretion, associated with enhanced interaction between ANXA2 and p11. Knockdown of ANXA2 or blocking membrane ANXA2 mitigated bleomycin-induced activation of nuclear factor (NF)-kappa B pathway and production of pro-inflammatory cytokine 1L-6 in lung epithelial cells. ANXA2-deficient (ANXA2(-/-) ) mice treated with bleomycin exhibit reduced pulmonary fibrosis along with decreased cytokine production compared with bleomycin-challenged wild-type mice. Further, the surface ANXA2 inhibitor TM601 could ameliorate fibrotic and inflammatory response in bleomycin-treated mice. Taken together, our results indicated that, in addition to disturbing autophagic flux, ANXA2 can contribute to bleomycin-induced pulmonary fibrosis by mediating inflammatory response.