T-cell immunoglobulin mucin-3 determines severity of liver ischemia/reperfusion injury in mice in a TLR4-dependent manner.
T-cell immunoglobulin mucin-3 determines severity of liver ischemia/reperfusion injury in mice in a TLR4-dependent manner.
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DOI：
10.1053/j.gastro.2010.07.003
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发表时间：
2010-12
期刊：
影响因子：
29.4
通讯作者：
Kupiec-Weglinski JW
中科院分区：
文献类型：
--
作者：
Uchida Y;Ke B;Freitas MC;Yagita H;Akiba H;Busuttil RW;Najafian N;Kupiec-Weglinski JW
新发现的T细胞免疫球蛋白粘蛋白（TIM）基因家族分子，由T细胞表达，调节宿主免疫和耐受性。虽然CD4+ T细胞介导先天免疫主导的肝缺血再灌注损伤（IRI），但其潜在机制尚不清楚。我们最近记录了TIM-1通路在肝脏IRI机制中的新功能，并发现TLR4激活起关键的触发作用。利用抗TIM-3抗体，我们研究了TIM-3信号在部分热肝缺血再灌注模型中的作用。与对照组相比，抗tim -3抗体治疗加重了肝损伤。组织学检查显示，抗tim -3 Ab增强肝细胞损伤，增加局部中性粒细胞浸润，促进局部T细胞/巨噬细胞积聚，促进肝细胞凋亡。治疗组肝内中性粒细胞活性、促炎细胞因子/趋化因子诱导及cleaved caspase-3/NF-NB/TLR4表达均升高。同时，抗TIM-3 Ab和抗半乳糖凝集素-9 （Gal-9； TIM-3配体）Ab增加了cona刺激的脾脏T细胞中IFN-γ的产生，以及cona刺激的巨噬细胞/T细胞共培养系统中tnf - α/IL-6的表达。有趣的是，抗tim -3 Ab治疗不影响tlr4缺陷（KO）小鼠的肝脏IRI。综上所述，TIM-3阻断加重了局部炎症和肝损伤，提示TIM-3/Gal-9信号在维持肝脏稳态中的重要性。TIM-3-TLR4交叉调节以tlr4依赖的方式决定肝脏IRI的严重程度，这一新发现对调节肝移植患者的组织先天反应和适应性反应具有潜在的重要性。因此，利用生理负T细胞对肝T细胞的共刺激信号可以最大限度地减少先天免疫介导的肝组织损伤。
The newly discovered T-cell immunoglobulin mucin (TIM) gene family molecules, expressed by T cells, regulate host immunity and tolerance. Although CD4+ T cells mediate innate immunity-dominated liver ischemia-reperfusion injury (IRI), the underlying mechanisms remain obscure. We have recently documented the novel function of TIM-1 pathway in the mechanism of liver IRI and also found that TLR4 activation plays a key triggering role. Using an anti-TIM-3 Ab, we now studied the role of TIM-3 signaling in the model of partial warm liver ischemia followed by reperfusion. Anti-TIM-3 Ab therapy exacerbated the liver damage, as compared with controls. Histological examination has revealed that anti-TIM-3 Ab augmented the hepatocellular damage, increased local neutrophil infiltration, facilitated local accumulation of T cells/macrophages and promoted liver cell apoptosis. Intrahepatic neutrophil activity, induction of pro-inflammatory cytokines/chemokines and expression of cleaved caspase-3/NF-NB/TLR4 were all increased in the treatment group. In parallel, anti-TIM-3 Ab and anti-galectin-9 (Gal-9; TIM-3 ligand) Ab increased IFN-γ production in ConA-stimulated spleen T cells, and TNFα/IL-6 expression in ConA-stimulated macrophage/T cell co-culture system. Interestingly, anti-TIM-3 Ab treatment did not affect liver IRI in TLR4-deficient (KO) mice. In conclusion, TIM-3 blockade exacerbated local inflammation and liver damage, suggesting importance of TIM-3/Gal-9 signaling in the maintenance of hepatic homeostasis. TIM-3-TLR4 cross regulation determined the severity of liver IRI in TLR4-dependent manner, a novel finding of potential importance to modulate tissue innate vs. adaptive responses in liver transplant patients. Thus, harnessing physiological negative T cell co-stimulation signaling on hepatic T cells may minimize innate immunity-mediated liver tissue damage.
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影响因子：
--
作者：
HERNANDEZ, LA;GRISHAM, MB;GRANGER, DN
通讯作者：
GRANGER, DN
DOI：
10.1084/jem.20061097
发表时间：
2006-11-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
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通讯作者：
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影响因子：
4.4
作者：
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通讯作者：
Azuma, Miyuki
影响因子：
24.1
作者：
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通讯作者：
Ma, Chunhong
影响因子：
15.9
作者：
COLLETTI, LM;REMICK, DG;CAMPBELL, DA
通讯作者：
CAMPBELL, DA