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Glycogen synthase kinase 3β promotes liver innate immune activation by restraining AMP-activated protein kinase activation.
糖原合成酶激酶 3 β 通过抑制 AMP 激活的蛋白激酶激活促进肝脏先天免疫激活。
AMP-activated protein kinase Glycogen synthase kinase 3 beta IL-10 Inflammation Ischaemia–reperfusion injury Macrophage Small heterodimer partner Toll-like receptor
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摘要

BACKGROUND & AIMS:Glycogen synthase kinase 3β (Gsk3β [Gsk3b]) is a ubiquitously expressed kinase with distinctive functions in different types of cells. Although its roles in regulating innate immune activation and ischaemia and reperfusion injuries (IRIs) have been well documented, the underlying mechanisms remain ambiguous, in part because of the lack of cell-specific tools in vivo.
METHODS:We created a myeloid-specific Gsk3b knockout (KO) strain to study the function of Gsk3β in macrophages in a murine liver partial warm ischaemia model.
RESULTS:Compared with controls, myeloid Gsk3b KO mice were protected from IRI, with diminished proinflammatory but enhanced anti-inflammatory immune responses in livers. In bone marrow-derived macrophages, Gsk3β deficiency resulted in an early reduction of Tnf gene transcription but sustained increase of Il10 gene transcription on Toll-like receptor 4 stimulation in vitro. These effects were associated with enhanced AMP-activated protein kinase (AMPK) activation, which led to an accelerated and higher level of induction of the novel innate immune negative regulator small heterodimer partner (SHP [Nr0b2]). The regulatory function of Gsk3β on AMPK activation and SHP induction was confirmed in wild-type bone marrow-derived macrophages with a Gsk3 inhibitor. Furthermore, we found that this immune regulatory mechanism was independent of Gsk3β Ser9 phosphorylation and the phosphoinositide 3-kinase-Akt signalling pathway. In vivo, myeloid Gsk3β deficiency facilitated SHP upregulation by ischaemia-reperfusion in liver macrophages. Treatment of Gsk3b KO mice with either AMPK inhibitor or SHP small interfering RNA before the onset of liver ischaemia restored liver proinflammatory immune activation and IRI in these otherwise protected hosts. Additionally, pharmacological activation of AMPK protected wild-type mice from liver IRI, with reduced proinflammatory immune activation. Inhibition of the AMPK-SHP pathway by liver ischaemia was demonstrated in tumour resection patients.
CONCLUSIONS:Gsk3β promotes innate proinflammatory immune activation by restraining AMPK activation.
LAY SUMMARY:Glycogen synthase kinase 3β promotes macrophage inflammatory activation by inhibiting the immune regulatory signalling of AMP-activated protein kinase and the induction of small heterodimer partner. Therefore, therapeutic targeting of glycogen synthase kinase 3β enhances innate immune regulation and protects liver from ischaemia and reperfusion injury.

译文

背景与目的: 糖原合成酶激酶 3 β (gsk3 β [Gsk3b]) 是一种在不同类型细胞中具有独特功能的泛素表达激酶。虽然它在调节先天免疫激活和缺血再灌注损伤 (IRIs) 中的作用已经被很好地证明了,但是潜在的机制仍然不明确, 部分原因是体内缺乏细胞特异性工具。
方法: 我们创造了一种髓系特异性 Gsk3b 基因敲除 (KO) 菌株,以研究在小鼠肝脏部分热缺血模型中巨噬细胞中 gsk3 β 的功能。
结果: 与对照组相比,骨髓型 Gsk3b KO 小鼠免受 IRI 的影响,其促炎作用减弱,但肝脏的抗炎免疫反应增强。在骨髓来源的巨噬细胞中,gsk3 β 缺乏导致 Tnf 基因转录的早期减少,但在体外 Toll 样受体 4 刺激下 Il10 基因转录的持续增加。这些效果与增强的 AMP-活化蛋白激酶 (AMPK) 活化有关, 这导致了新的先天免疫负调控因子小异源二聚体伴侣 (SHP [Nr0b2]) 的加速和更高水平的诱导。Gsk3 β 对 AMPK 激活和 SHP 诱导的调节功能在带有 Gsk3 抑制剂的野生型骨髓来源巨噬细胞中得到证实。此外,我们发现这种免疫调节机制独立于 gsk3 β Ser9 磷酸化和磷酸肌醇 3-激酶-akt 信号通路。在体内,骨髓 gsk3 β 缺乏通过肝脏巨噬细胞缺血再灌注促进 SHP 上调。在肝脏缺血开始前,用 AMPK 抑制剂或 SHP 小干扰 RNA 处理 Gsk3b KO 小鼠,恢复了这些受保护宿主的肝脏促炎免疫激活和 IRI。此外,AMPK 的药理激活保护野生型小鼠免受肝脏 IRI,减少促炎免疫激活。肝缺血抑制 AMPK-SHP 通路在 resection 切除患者中被证明。
结论: gsk3 β 通过抑制 AMPK 活化促进先天促炎免疫活化。
总结: 糖原合成酶激酶 3 β 通过抑制 AMP-活化蛋白激酶的免疫调节信号和小异源二聚体伴侣的诱导促进巨噬细胞炎症激活。因此,治疗靶向糖原合成酶激酶 3 β 增强先天免疫调节,保护肝脏免受缺血和再灌注损伤。

AMP-activated protein kinase

内分泌 临床研究术语
概述  :  

5'AMP 激活的蛋白激酶或AMPK或5'腺苷单磷酸激活的蛋白激酶是一种酶,在细胞能量稳态中发挥作用,主要是在细胞能量达到一定水平时激活葡萄糖和脂肪酸的摄取和氧化。它属于高度保守的真核蛋白质家族,其直向同源物是酵母中的SNF1和植物中的SnRK1。它由三种蛋白质(亚基)组成,它们共同构成一种功能酶,从酵母到人类都是保守的。它在许多组织中表达,包括肝,脑和骨骼肌。 功能 当AMPK磷酸化乙酰辅酶A羧化酶 1(ACC1)或固醇调节

activated   英 /'æktɪveɪtɪd/   美 /'æktə,vetɪd/

释    义   adj. 活性化的;活泼的

               v. 使激活;使活动起来;有生气(activate的过去分词)

同根词   active adj. 积极的;活跃的;主动的;有效的;现役的

               actively adv. 积极地;活跃地

               active n. 主动语态;积极分子

例    句   What I want you to remember is that specific sub-populations of cells get activated, the activation results in a specific response. 我希望你们记住的是,一些特定的细胞亚群受到刺激时,被激活细胞将引起特定的应答。

 

protein   英 /ˈprəʊtiːn/   美 /ˈproʊtiːn/

释    义   n. 蛋白质;朊

               adj. 蛋白质的

例    句   Each codon either codes for an amino acid or tells the cell to stop making a protein chain.每一个密码子或者编码一种氨基酸,或者告诉这些细胞停止生产这个蛋白质链。

 

kinase   英 /ˈkaɪneɪz/   美 /ˈkɪnneɪz/

释    义   n. [生化] 激酶;致活酶

例    句   The scientists successfully identified the small enzyme molecule responsible, a gene called focal adhesion kinase.科学家成功分离出这种小小的酶分子,基因学上称之为局部粘着激酶。

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