IL-17A 在加剧辐射诱导的肺损伤中的作用：通过 PP2A-mTOR 通路的自噬损伤

IF 4.6 2区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Biochimica et biophysica acta. Molecular cell research Pub Date : 2024-10-20 DOI:10.1016/j.bbamcr.2024.119864

Liangzhong Liu , GuangMing Yi , Xiaohong Li , Cai Chen , Kehong Chen , Hengqiu He , Jinjin Li , Fanghao Cai , Yuan Peng , Zhenzhou Yang , Xiaoyue Zhang

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引用次数: 0

摘要

目的：放疗引起的肺损伤（RILI）是放疗的一种严重并发症，而 IL-17A 在这一过程中的作用尚不十分清楚。虽然已证明 IL-17A 可调节自噬，但关于其激活或抑制自噬的报道却相互矛盾。本研究探讨了 IL-17A 在 RILI 中的作用及其通过 PP2A-mTOR 途径对自噬的影响，重点是 PP2A B56α 亚基：方法：将 C57BL/6J 小鼠和人肺上皮细胞（BEAS-2B）暴露于含有或不含重组 IL-17A 的辐射中。使用 Western 印迹、免疫荧光和自噬通量测定分析自噬标记物。测定了 PP2A 的活性，特别是 B56α 亚基。使用 PP2A 激动剂（DT-061）验证其在逆转 IL-17A 介导的自噬抑制中的作用：结果：IL-17A通过抑制PP2A的活性，特别是通过下调B56α亚基，导致mTOR激活和自噬体形成减少，从而抑制了暴露于辐射的肺上皮细胞的自噬。使用 DT-061 治疗可恢复自噬活性并提高细胞活力。这些发现与IL-17A在某些情况下抑制自噬的报道一致，而其他研究则显示了相反的作用：结论：IL-17A通过PP2A B56α-mTOR通路抑制RILI中的自噬，加剧肺损伤。要明确IL-17A在不同细胞类型和条件下的作用，还需要进一步的研究。以IL-17A-PP2A B56α-mTOR轴为靶点可能会为RILI的治疗提供新的治疗策略。

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IL-17A's role in exacerbating radiation-induced lung injury: Autophagy impairment via the PP2A-mTOR pathway

Objective

Radiation-induced lung injury (RILI) is a serious complication of radiotherapy, and the role of IL-17A in this process is not well understood. While IL-17A has been shown to modulate autophagy, conflicting reports exist regarding its activation or inhibition of autophagy. This study investigates the role of IL-17A in RILI and its effects on autophagy via the PP2A-mTOR pathway, with a focus on the PP2A B56α subunit.

Methods

C57BL/6J mice and human lung epithelial cells (BEAS-2B) were exposed to radiation with or without recombinant IL-17A. Autophagy markers were analyzed using Western blotting, immunofluorescence, and autophagy flux assays. PP2A activity, specifically the B56α subunit, was measured. A PP2A agonist (DT-061) was used to verify its role in reversing IL-17A-mediated autophagy inhibition.

Results

IL-17A inhibited autophagy in lung epithelial cells exposed to radiation by suppressing PP2A activity, particularly through downregulation of the B56α subunit, leading to mTOR activation and reduced autophagosome formation. Treatment with DT-061 restored autophagic activity and improved cell viability. These findings align with reports suggesting that IL-17A inhibits autophagy in certain contexts, while other studies have shown opposing effects.

Conclusion

IL-17A inhibits autophagy in RILI through the PP2A B56α-mTOR pathway, exacerbating lung damage. Further research is needed to clarify the role of IL-17A in different cell types and conditions. Targeting the IL-17A-PP2A B56α-mTOR axis may offer new therapeutic strategies for RILI management.

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来源期刊

Biochimica et biophysica acta. Molecular cell research 生物-生化与分子生物学

CiteScore

10.00

自引率

2.00%

发文量

151

审稿时长

44 days

期刊介绍： BBA Molecular Cell Research focuses on understanding the mechanisms of cellular processes at the molecular level. These include aspects of cellular signaling, signal transduction, cell cycle, apoptosis, intracellular trafficking, secretory and endocytic pathways, biogenesis of cell organelles, cytoskeletal structures, cellular interactions, cell/tissue differentiation and cellular enzymology. Also included are studies at the interface between Cell Biology and Biophysics which apply for example novel imaging methods for characterizing cellular processes.