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Glycogen synthase kinase 3β promotes liver innate immune activation by restraining AMP-activated protein kinase activation
Journal of Hepatology ( IF 26.8 ) Pub Date : 2018-07-01 , DOI: 10.1016/j.jhep.2018.01.036
Haoming Zhou 1 , Han Wang 1 , Ming Ni 1 , Shi Yue 2 , Yongxiang Xia 2 , Ronald W Busuttil 3 , Jerzy W Kupiec-Weglinski 3 , Ling Lu 2 , Xuehao Wang 2 , Yuan Zhai 3
Affiliation  

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.

中文翻译:


糖原合酶激酶 3β 通过抑制 AMP 激活的蛋白激酶激活来促进肝脏先天免疫激活



背景与目的 糖原合酶激酶 3β (Gsk3β [Gsk3b]) 是一种普遍表达的激酶,在不同类型的细胞中具有独特的功能。尽管其在调节先天免疫激活以及缺血和再灌注损伤(IRIs)方面的作用已得到充分证明,但其潜在机制仍然不明确,部分原因是体内缺乏细胞特异性工具。方法我们创建了骨髓特异性 Gsk3b 敲除 (KO) 菌株,以研究小鼠肝脏部分热缺血模型中巨噬细胞中 Gsk3β 的功能。结果与对照组相比,髓系 Gsk3b KO 小鼠免受 IRI 影响,肝脏中的促炎免疫反应减弱,但抗炎免疫反应增强。在骨髓源性巨噬细胞中,Gsk3β 缺陷导致 Tnf 基因转录早期减少,但在体外刺激 Toll 样受体 4 时,Il10 基因转录持续增加。这些效应与增强的 AMP 激活蛋白激酶 (AMPK) 激活相关,从而导致新型先天免疫负调节小异二聚体伙伴 (SHP [Nr0b2]) 的诱导加速且水平更高。 Gsk3β 对 AMPK 激活和 SHP 诱导的调节功能在具有 Gsk3 抑制剂的野生型骨髓源性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 Gsk3β Ser9 磷酸化和磷酸肌醇 3-激酶-Akt 信号通路。在体内,骨髓 Gsk3β 缺乏通过肝脏巨噬细胞缺血再灌注促进 SHP 上调。在肝缺血发生前,用 AMPK 抑制剂或 SHP 小干扰 RNA 治疗 Gsk3b KO 小鼠,可恢复这些受保护宿主的肝脏促炎性免疫激活和 IRI。 此外,AMPK 的药理学激活可保护野生型小鼠免受肝脏 IRI 的影响,并减少促炎性免疫激活。在肿瘤切除患者中证实了肝脏缺血对 AMPK-SHP 通路的抑制。结论 Gsk3β 通过抑制 AMPK 激活来促进先天促炎性免疫激活。糖原合酶激酶 3β 通过抑制 AMP 激活蛋白激酶的免疫调节信号和小异二聚体伙伴的诱导来促进巨噬细胞炎症激活。因此,以糖原合成酶激酶 3β 为靶点的治疗可增强先天免疫调节并保护肝脏免受缺血和再灌注损伤。
更新日期:2018-07-01
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