Functional crosstalk between myeloid Foxo1-β-catenin axis and Hedgehog/Gli1 signaling in oxidative stress response.
Functional crosstalk between myeloid Foxo1-β-catenin axis and Hedgehog/Gli1 signaling in oxidative stress response.
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DOI：
10.1038/s41418-020-00695-7
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发表时间：
2021-05
影响因子：
12.4
通讯作者：
Ke B
中科院分区：
文献类型：
--
作者：
Li C;Sheng M;Lin Y;Xu D;Tian Y;Zhan Y;Jiang L;Coito AJ;Busuttil RW;Farmer DG;Kupiec-Weglinski JW;Ke B
Foxo 1转录因子是一种进化上保守的细胞代谢、氧化应激、炎症和凋亡调节因子。已知Hedgehog/Gli信号传导的激活调节细胞生长、分化和免疫功能。然而，相互作用的细胞信号网络抑制氧化应激反应和坏死性凋亡的分子机制仍然知之甚少。在这里，我们报告骨髓特异性Foxo 1基因敲除（Foxo 1 M-KO）小鼠抗氧化应激诱导的肝细胞损伤，减少巨噬细胞/中性粒细胞浸润，和促炎介质在肝脏缺血/再灌注损伤（IRI）。Foxo 1 M-KO增强β-catenin介导的Gli 1/Snail活性，并降低IR应激肝脏中受体相互作用蛋白激酶3（RIPK 3）和NIMA相关激酶7（NEK 7）/NLRP 3的表达。Foxo 1 M-KO肝脏中Gli 1的破坏使肝功能恶化，Snail减少，RIPK 3和NEK 7/NLRP 3增加。从机制上讲，巨噬细胞Foxo 1和β-连环蛋白共定位于细胞核中，从而Foxo 1在炎症条件下与T细胞因子（TCF）竞争与β-连环蛋白的相互作用。通过Foxo 1缺失破坏Foxo 1-β-catenin轴增强β-catenin/TCF结合，激活Gli 1/Snail信号传导，导致抑制RIPK 3和NEK 7/NLRP 3。此外，巨噬细胞Gli 1或Snail敲除激活RIPK 3并增加肝细胞坏死性凋亡，而巨噬细胞RIPK 3消融减少NEK 7/NLRP 3驱动的炎症反应。我们的研究结果强调了骨髓Foxo 1-β-catenin轴调节Hedgehog/Gli 1功能的新型分子机制，该功能是氧化应激诱导的肝脏炎症和坏死性凋亡的关键。
Foxo1 transcription factor is an evolutionarily conserved regulator of cell metabolism, oxidative stress, inflammation, and apoptosis. Activation of Hedgehog/Gli signaling is known to regulate cell growth, differentiation, and immune function. However, the molecular mechanisms by which interactive cell signaling networks restrain oxidative stress response and necroptosis are still poorly understood. Here, we report that myeloid-specific Foxo1 knockout (Foxo1M-KO) mice were resistant to oxidative stress-induced hepatocellular damage with reduced macrophage/neutrophil infiltration, and proinflammatory mediators in liver ischemia/reperfusion injury (IRI). Foxo1M-KO enhanced β-catenin-mediated Gli1/Snail activity, and reduced receptor-interacting protein kinase 3 (RIPK3) and NIMA-related kinase 7 (NEK7)/NLRP3 expression in IR-stressed livers. Disruption of Gli1 in Foxo1M-KO livers deteriorated liver function, diminished Snail, and augmented RIPK3 and NEK7/NLRP3. Mechanistically, macrophage Foxo1 and β-catenin colocalized in the nucleus, whereby the Foxo1 competed with T-cell factor (TCF) for interaction with β-catenin under inflammatory conditions. Disruption of the Foxo1–β-catenin axis by Foxo1 deletion enhanced β-catenin/TCF binding, activated Gli1/Snail signaling, leading to inhibited RIPK3 and NEK7/NLRP3. Furthermore, macrophage Gli1 or Snail knockout activated RIPK3 and increased hepatocyte necroptosis, while macrophage RIPK3 ablation diminished NEK7/NLRP3-driven inflammatory response. Our findings underscore a novel molecular mechanism of the myeloid Foxo1–β-catenin axis in regulating Hedgehog/Gli1 function that is key in oxidative stress-induced liver inflammation and necroptosis.
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DOI：
10.1016/j.bbrc.2008.11.043
发表时间：
2009-01-09
影响因子：
3.1
作者：
Ito, Yu;Daitoku, Hiroaki;Fukamizu, Akiyoshi
通讯作者：
Fukamizu, Akiyoshi
在细胞死亡和炎症的串扰中进行了编程坏死。
影响因子：
29.7
作者：
Chan FK;Luz NF;Moriwaki K
通讯作者：
Moriwaki K
影响因子：
11.4
作者：
Fan, WuQiang;Morinaga, Hidetaka;Olefsky, Jerrold M.
通讯作者：
Olefsky, Jerrold M.
影响因子：
4.6
作者：
Minsart, Charlotte;Liefferinckx, Claire;Gustot, Thierry
通讯作者：
Gustot, Thierry
小鼠肝脏缺血/再灌注损伤中的 HO-1-STAT3 轴：通过 PI3K/PTEN 信号传导调节 TLR4 先天反应。
影响因子：
25.7
作者：
Ke, Bibo;Shen, Xiu-Da;Ji, Haofeng;Kamo, Naoko;Gao, Feng;Freitas, Maria Cecilia S.;Busuttil, Ronald W.;Kupiec-Weglinski, Jerzy W.
通讯作者：
Kupiec-Weglinski, Jerzy W.