Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease.
Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease.
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DOI：
10.1002/hep.28680
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发表时间：
2016-10
期刊：
影响因子：
13.5
通讯作者：
Szabo, Gyongyi
中科院分区：
文献类型：
--
作者：
Bukong, Terence N.;Iracheta-Vellve, Arvin;Saha, Banishree;Ambade, Aditya;Satishchandran, Abhishek;Gyongyosi, Benedek;Lowe, Patrick;Catalano, Donna;Kodys, Karen;Szabo, Gyongyi
酒精性肝病(ALD)的谱系是死亡的主要原因，现有的治疗方法有限。因为酒精针对肝细胞和免疫细胞中的许多信号通路，所以识别一个调节多种信号过程的主调控靶点是很有吸引力的。在这篇报告中，我们评估了脾酪氨酸激酶(SYK)的作用，它是一种非受体酪氨酸激酶，在参与ALD发病机制的多个促炎信号通路中起着中心调节作用。使用代表人类ALD发展过程中不同阶段的小鼠疾病模型，我们发现在所有这些模型中，酒精都能诱导肝脏中SYK的激活，包括肝细胞和肝脏单个核细胞。此外，与对照组相比，ALD/酒精性肝炎患者的肝脏样本和外周血单核细胞中也出现了显著的SYK激活。体内SYK激活的功能抑制消除了酒精诱导的肝脏中性粒细胞的浸润，常驻免疫细胞的激活，以及炎症小体和ERK1/2介导的NF-κB的激活。值得注意的是，抑制SYK的激活可以减少酒精诱导的肝脏脂肪变性和IRF3介导的细胞凋亡。我们的研究结果表明，在ALD的不同阶段，SYK磷酸化在调节免疫细胞驱动的肝脏炎症、肝细胞死亡和脂肪变性方面具有新的、功能和多细胞的作用。这些新的发现强调了SYK作为治疗酒精性脂肪性肝炎的一个潜在的多功能靶点。
The spectrum of alcoholic liver disease (ALD) is a major cause of mortality with limited therapies available. Because alcohol targets numerous signaling pathways in hepatocytes and in immune cells, the identification of a master regulatory target that modulates multiple signaling processes is attractive. In this report, we assessed the role of spleen tyrosine kinase (SYK), a non-receptor tyrosine kinase, which has a central modulatory role in multiple pro-inflammatory signaling pathways involved in the pathomechanism of ALD. Using mouse disease models that represent various phases in the progression of human ALD, we found that alcohol, in all of these models, induced SYK activation in the liver, both in hepatocytes and liver mononuclear cells. Further, significant SYK activation also occurred in liver samples and peripheral blood mononuclear cells of patients with ALD/alcoholic hepatitis compared to controls. Functional inhibition of SYK activation in vivo abrogated alcohol-induced hepatic neutrophil infiltration, resident immune cell activation, as well as inflammasome and ERK1/2-mediated NF-κB activation in mice. Strikingly, inhibition of SYK activation diminished alcohol-induced hepatic steatosis and IRF3-mediated apoptosis. Our data demonstrate a novel, functional, and multicellular role for SYK phosphorylation in modulating immune cell-driven liver inflammation, hepatocyte cell death, and steatosis at different stages of ALD. These novel findings highlight SYK as a potential multifunctional target in the treatment of alcoholic steatohepatitis.
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影响因子：
8
作者：
Lee CK;Yang Y;Chen C;Liu J
通讯作者：
Liu J
DOI：
10.1124/jpet.106.109058
发表时间：
2006-12-01
影响因子：
3.5
作者：
Braselmann, Sylvia;Taylor, Vanessa;Masuda, Esteban S.
通讯作者：
Masuda, Esteban S.
DOI：
10.2174/187221312800166895
发表时间：
2012-01-01
影响因子：
4.2
作者：
Moretto, Alessandro F.;Dehnhardt, Christoph;Thorarensen, Atli
通讯作者：
Thorarensen, Atli
影响因子：
13.5
作者：
Bukong, Terence N.;Kodys, Karen;Szabo, Gyongyi
通讯作者：
Szabo, Gyongyi
DOI：
10.1111/j.1530-0277.2010.01399.x
发表时间：
2011-05
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Miller AM;Horiguchi N;Jeong WI;Radaeva S;Gao B
通讯作者：
Gao B