通过 p120-Catenin 介导的 mTOR 信号通路增强巨噬细胞的自噬作用

IF 3.6 3区 医学 Q2 IMMUNOLOGY
Suganya Kanmani, Xue-Min Song, Paulraj Kanmani, Xiao-Jing Wu, Xiao-Di Tan, Jing Liu, Ji-Ping Wang, Richard D Minshall, Guochang Hu
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引用次数: 0

摘要

自噬是败血症免疫反应的关键调节因子。巨噬细胞是先天性免疫和适应性免疫的重要组成部分。在这项研究中,我们深入研究了 p120-catenin(p120)在巨噬细胞应对内毒素刺激时协调自噬的复杂作用。在 J774A.1 巨噬细胞和小鼠骨髓源性巨噬细胞中,消耗 p120 能有效抑制 LPS 诱导的自噬。LPS 不仅增强了 p120 与 L 链 3(LC3)I/II 之间的相互作用,还促进了 p120 与哺乳动物雷帕霉素靶标(mTOR)的结合。p120 的耗竭也增强了 LPS 诱导的巨噬细胞凋亡,这可以从裂解的 Caspase 3、7-氨基放线菌素 D 染色和 TUNEL 检测水平的增加得到证明。值得注意的是,抑制自噬可以逆转过表达 p120 的巨噬细胞在 LPS 刺激下凋亡的减少。此外,在 LPS 攻击小鼠的肺泡巨噬细胞中,p120 的消融抑制了自噬,加剧了细胞凋亡。总之,我们的研究结果有力地表明,p120 在脓毒症中通过调节 mTOR/ULK1 信号通路,在促进巨噬细胞自噬的同时阻碍其凋亡方面发挥着关键作用。这凸显了以巨噬细胞 p120 为靶点作为治疗炎症性疾病的创新疗法的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Enhancement of Autophagy in Macrophages via the p120-Catenin-Mediated mTOR Signaling Pathway.

Autophagy serves as a critical regulator of immune responses in sepsis. Macrophages are vital constituents of both innate and adaptive immunity. In this study, we delved into the intricate role of p120-catenin (p120) in orchestrating autophagy in macrophages in response to endotoxin stimulation. Depletion of p120 effectively suppressed LPS-induced autophagy in both J774A.1 macrophages and murine bone marrow-derived macrophages. LPS not only elevated the interaction between p120 and L chain 3 (LC3) I/II but also facilitated the association of p120 with mammalian target of rapamycin (mTOR). p120 depletion in macrophages by small interfering RNA reduced LPS-induced dissociation of mTOR and Unc-51-like kinase 1 (ULK1), leading to an increase in the phosphorylation of ULK1. p120 depletion also enhanced LPS-triggered macrophage apoptosis, as evidenced by increased levels of cleaved caspase 3, 7-aminoactinomycin D staining, and TUNEL assay. Notably, inhibiting autophagy reversed the decrease in apoptosis caused by LPS stimulation in macrophages overexpressing p120. Additionally, the ablation of p120 inhibited autophagy and accentuated apoptosis in alveolar macrophages in LPS-challenged mice. Collectively, our findings strongly suggest that p120 plays a pivotal role in fostering autophagy while concurrently hindering apoptosis in macrophages, achieved through modulation of the mTOR/ULK1 signaling pathway in sepsis. This underscores the potential of targeting macrophage p120 as an innovative therapeutic avenue for treating inflammatory disorders.

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来源期刊
Journal of immunology
Journal of immunology 医学-免疫学
CiteScore
8.20
自引率
2.30%
发文量
495
审稿时长
1 months
期刊介绍: The JI publishes novel, peer-reviewed findings in all areas of experimental immunology, including innate and adaptive immunity, inflammation, host defense, clinical immunology, autoimmunity and more. Special sections include Cutting Edge articles, Brief Reviews and Pillars of Immunology. The JI is published by The American Association of Immunologists (AAI)
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