Autophagy Contributes to the Rapamycin-Induced Improvement of Otitis Media.
Autophagy Contributes to the Rapamycin-Induced Improvement of Otitis Media.
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自噬有助于雷帕霉素诱导的中耳炎的改善
DOI：
10.3389/fncel.2021.753369
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发表时间：
2021
影响因子：
5.3
通讯作者：
Zheng QY
中科院分区：
文献类型：
--
作者：
Xie D;Zhao T;Zhang X;Kui L;Wang Q;Wu Y;Zheng T;Ma P;Zhang Y;Molteni H;Geng R;Yang Y;Li B;Zheng QY
中耳炎（OM）是一种普遍性疾病，涉及听力损失和严重的并发症。在我们先前的研究中，我们成功地建立了一个人OM小鼠模型，使用TLR 2-/-的Tlr 2 tm 1 Kir（TLR 2-/-）小鼠中耳（ME）接种链球菌肽聚糖多糖（PGPS）。在这项研究中，我们发现OM小鼠的听力损失和OM感染在用雷帕霉素（RPM）治疗后显著减轻，RPM是一种广泛使用的RPM复合物1（mTORC 1）抑制剂和自噬诱导剂的机制靶点。首先，我们通过评估p-S6、Raptor和mTOR蛋白表达来测试mTORC 1的活性。结果表明，注射PGPS后，TLR 2-/-小鼠p-S6、Raptor和mTOR蛋白表达水平降低。此外，我们的数据表明，自噬体蛋白LC 3-II，Beclin-1，ATG 7和自噬底物蛋白p62在OM小鼠中的积累水平高于OM阴性小鼠。与OM阴性小鼠相比，OM小鼠中溶酶体相关蛋白LAMP 1、组织蛋白酶B和组织蛋白酶D的表达增加。Rab 7和Syntaxin 17是自噬体与溶酶体融合所必需的，在OM小鼠中减少。此外，数据还描述了RPM处理后p-S6、mTOR和Raptor的蛋白表达水平低于PGPS组。RPM处理后LC 3-II、Beclin-1和ATG 7的积累减少，Rab 7和Syntaxin 17的表达增加。我们的研究结果表明，自噬损伤参与PGPS诱导的OM和RPM改善OM至少部分通过减轻自噬损伤。通过RPM调节自噬活性可能是OM的有效治疗策略。
Otitis media (OM) is a pervasive disease that involves hearing loss and severe complications. In our previous study, we successfully established a mouse model of human OM using Tlr2tm1Kir (TLR2–/–) mice with middle ear (ME) inoculation of streptococcal peptidoglycan-polysaccharide (PGPS). In this study, we found that hearing loss and OM infections in OM mice were significantly alleviated after treatment with rapamycin (RPM), a widely used mechanistic target of RPM complex 1 (mTORC1) inhibitor and autophagy inducer. First of all, we tested the activity of mTORC1 by evaluating p-S6, Raptor, and mTOR protein expression. The data suggested that the protein expression level of p-S6, Raptor and mTOR are decreased in TLR2–/– mice after the injection of PGPS. Furthermore, our data showed that both the autophagosome protein LC3-II, Beclin-1, ATG7, and autophagy substrate protein p62 accumulated at higher levels in mice with OM than in OM-negative mice. The expression of lysosomal-associated proteins LAMP1, Cathepsin B, and Cathepsin D increased in the OM mice compared with OM-negative mice. Rab7 and Syntaxin 17, which is necessary for the fusion of autophagosomes with lysosomes, are reduced in the OM mice. In addition, data also described that the protein expression level of p-S6, mTOR and Raptor are lower than PGPS group after RPM treatment. The accumulation of LC3-II, Beclin-1, and ATG7 are decreased, and the expression of Rab7 and Syntaxin 17 are increased significantly after RPM treatment. Our results suggest that autophagy impairment is involved in PGPS-induced OM and that RPM improves OM at least partly by relieving autophagy impairment. Modulating autophagic activity by RPM may be a possible effective treatment strategy for OM.
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