Alveolar macrophage-derived exosomal tRF-22-8BWS7K092 activates Hippo signaling pathway to induce ferroptosis in acute lung injury.
Alveolar macrophage-derived exosomal tRF-22-8BWS7K092 activates Hippo signaling pathway to induce ferroptosis in acute lung injury.
复制标题
DOI：
10.1016/j.intimp.2022.108690
复制
发表时间：
2022-03
影响因子：
5.6
通讯作者：
Weixi Wang;Lin Zhu;Hui-Ting Li;W. Ren;Ran Zhuo;Chencheng Feng;Yuting He;Yubo Hu;Cong Ye
中科院分区：
文献类型：
--
作者：
Weixi Wang;Lin Zhu;Hui-Ting Li;W. Ren;Ran Zhuo;Chencheng Feng;Yuting He;Yubo Hu;Cong Ye
肺泡巨噬细胞（alveolar macrophages，AM）在急性肺损伤（acute lung injury，ALI）中起着指示性作用.外泌体作为信号分子通过释放RNA来调节细胞与细胞之间的通讯。转移RNA衍生片段（tRFs）通过铁凋亡在多种疾病中具有潜在的功能。本研究旨在揭示AM来源的外泌体tRFs在ALI中的作用及其与铁凋亡的关系。进行RNA测序以鉴定ALI小鼠的支气管肺泡灌洗液（BALF）外泌体中的tRF谱。干扰后的候选tRFs在AM或肺泡上皮细胞（MLE-12）的表达，氧化应激和铁蛋白相关蛋白的表达的影响进行了检测。RNA测序鉴定了4个上调和10个下调的差异表达tRF（DEtRF），其中tRF-22- 8BWS 7 K 092在LPS诱导的巨噬细胞来源的外泌体（LPS-exo）中表达显著增加。Hippo信号通路是DEtRF最显著富集的KEGG通路。LPS-exo抑制细胞活力和GPX 4和FTH 1的表达，并增强MLE-12细胞的氧化应激。LPS-exo对MLE-12细胞存活率的抑制作用可被铁凋亡抑制剂逆转，而tRF-22- 8BWS 7 K 092抑制剂可逆转LPS-exo对MLE-12细胞的上述作用。此外，tRF-22- 8BWS 7 K 092还可通过与Wnt 5 B结合激活Hippo信号通路，诱导MLE-12细胞发生铁凋亡。AM衍生的外泌体tRF-22- 8BWS 7 K 092激活Hippo信号通路以诱导铁凋亡，从而有助于ALI的发病机制。
BackgroundAlveolar macrophages (AMs) play a demonstrative role in acute lung injury (ALI). Exosomes act as signaling molecules to regulate cell-to-cell communication by releasing RNAs. Transfer RNA-derived fragments (tRFs) possess potential functions in multiple diseases through ferroptosis. The present study aims to reveal the role of AM-derived exosomal tRFs in ALI and to identify the relationship to ferroptosis.MethodsALI mice model was established by lipopolysaccharide (LPS) induction. RNA sequencing was performed to identify the tRFs profile in bronchoalveolar lavage fluid (BALF) exosomes of ALI mice. After interfering with the expression of candidate tRFs in AMs or alveolar epithelial cells (MLE-12), the effect of oxidative stress and expression of ferroptosis-related proteins were detected.ResultsExosomes isolated from BALF of ALI mice were dominated by a macrophage immunophenotype. RNA-sequencing identified 4 up- and 10 down-regulated differentially expressed tRFs (DEtRFs), among which tRF-22-8BWS7K092 expression was significantly increased in LPS-induced macrophage-derived exosomes (LPS-exo). Hippo signaling pathway was the most significantly enriched KEGG pathways for DEtRFs. LPS-exo inhibited cell viability and the expression of GPX4 and FTH1, and enhanced oxidative stress in MLE-12 cells. Ferroptosis inhibitor reversed the inhibition of LPS-exo on cell viability and tRF-22-8BWS7K092 inhibitor rescued above effect of LPS-exo on MLE-12 cells. Besides, tRF-22-8BWS7K092 could activate Hippo signaling pathway by binding Wnt5B, inducing ferroptosis in MLE-12 cells.ConclusionBALF exosomes of ALI mice were mainly derived from AMs. AM-derived exosomal tRF-22-8BWS7K092 activates the Hippo signaling pathway to induce ferroptosis, thus contributing to the pathogenesis of ALI.