T-cell immunoglobulin and mucin domain 4 (TIM-4) signaling in innate immune-mediated liver ischemia-reperfusion injury.
T-cell immunoglobulin and mucin domain 4 (TIM-4) signaling in innate immune-mediated liver ischemia-reperfusion injury.
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DOI：
10.1002/hep.27334
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发表时间：
2014-12
期刊：
影响因子：
13.5
通讯作者：
Kupiec-Weglinski, Jerzy W.
中科院分区：
文献类型：
--
作者：
Ji, Haofeng;Liu, Yuanxing;Zhang, Yu;Shen, Xiu-da;Gao, Feng;Busuttil, Ronald W.;Kuchroo, Vijay K.;Kupiec-Weglinski, Jerzy W.
肝缺血再灌注损伤（IRI）是一种先天免疫驱动的炎症反应，发生在多种临床情况下，包括肝切除、移植、创伤和休克。TIM-4是唯一不在T细胞上表达的TIM蛋白，在巨噬细胞和树突状细胞上发现。巨噬细胞TIM-4在先天免疫介导的疾病状态下吞噬凋亡/坏死小体中的调节功能尚不清楚。本研究主要关注TIM-4信号在肝脏热缺血（90min）和再灌注模型中的作用。缺血损伤通过应激肝细胞磷脂酰丝氨酸（PS）表达触发TIM-4表达，在再灌注6h达到峰值，与肝细胞最大损伤时间一致。用拮抗TIM-4 mAb治疗的TIM-4缺陷或WT小鼠对肝脏IRI具有耐药性，这可以通过降低盐水平和保存良好的肝脏结构来证明。TIM-4缺乏对肝脏的保护作用伴随着巨噬细胞浸润/化学吸引、吞噬和tlr2 /4/9依赖性信号的激活减少。与体内动力学相关，lps激活的骨髓源性巨噬细胞（BMM）在培养6h时检测到TIM-4诱导的峰值。为了模拟肝脏IRI，我们使用了过氧化氢坏死肝细胞，它很容易呈现PS。事实上，坏死肝细胞被WT （TIM-4+）有效捕获/吞噬，而不是被缺乏TIM-4的BMM捕获/吞噬。最后，在一个新建立的肝脏IRI模型中，在CD11b-DTR小鼠系统中，WT而不是TIM-4缺陷BMM的过继转移很容易重建局部炎症反应/肝细胞损伤。结论：我们的新发现证明了巨噬细胞特异性TIM-4激活在肝脏IRI机制中的重要性。巨噬细胞TIM-4可能是减少ir应激器官先天炎症反应的治疗靶点。
Hepatic ischemia-reperfusion injury (IRI), an innate immunity-driven inflammation response, occurs in multiple clinical settings including liver resection, transplantation, trauma, and shock. TIM-4, the only TIM protein not expressed on T cells, is found on macrophages and dendritic cells. The regulatory function of macrophage TIM-4 in the engulfment of apoptotic/necrotic bodies in innate immunity-mediated disease states remains unknown. This study focuses on putative role of TIM-4 signaling in a model of liver warm ischemia (90min) and reperfusion. The ischemia insult triggered TIM-4 expression by stressed hepatocellular phosphatidylserine (PS) presentation, peaking at 6h of reperfusion, and coinciding with the maximal hepatocellular damage. TIM-4-deficient or WT mice treated with antagonistic TIM-4 mAb were resistant against liver IRI, evidenced by diminished sALT levels and well-preserved hepatic architecture. Liver hepatoprotection rendered by TIM-4 deficiency was accompanied by diminished macrophage infiltration/chemoattraction, phagocytosis and activation of TLR2/4/9-dependent signaling. Correlating with in vivo kinetics, the peak of TIM-4 induction in LPS-activated bone marrow derived-macrophages (BMM) was detected in 6h cultures. To mimic liver IRI, we employed hydrogen peroxide-necrotic hepatocytes, which readily present PS. Indeed, necrotic hepatocytes were efficiently captured/engulfed by WT (TIM-4+) but not by TIM-4-deficient BMM. Finally, in a newly established model of liver IRI, adoptive transfer of WT but not TIM-4 deficient BMM readily recreated local inflammation response/hepatocellular damage in the CD11b-DTR mouse system. Conclusion: Our novel findings document the importance of macrophage-specific TIM-4 activation in the mechanism of hepatic IRI. Macrophage TIM-4 may represent a therapeutic target to minimize innate inflammatory responses in IR-stressed organs.
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DOI：
10.1002/wsbm.1158
发表时间：
2012-05-01
影响因子：
7.9
作者：
Holzhuetter, Hermann-Georg;Drasdo, Dirk;Henney, Adriano M.
通讯作者：
Henney, Adriano M.
DOI：
10.1111/j.1365-2362.1988.tb01053.x
发表时间：
1988-10-01
影响因子：
5.5
作者：
KAISER, S;GEROK, W;HAUSSINGER, D
通讯作者：
HAUSSINGER, D
影响因子：
3.5
作者：
MOORMAN, AFM;DEBOER, PAJ;LAMERS, WH
通讯作者：
LAMERS, WH
影响因子：
11.4
作者：
GEBHARDT, R;MECKE, D
通讯作者：
MECKE, D
DOI：
10.1038/icb.1977.26
发表时间：
1977-01-01
期刊：
AUSTRALIAN JOURNAL OF EXPERIMENTAL BIOLOGY AND MEDICAL SCIENCE
影响因子：
--
作者：
KUCHEL, PW;ROBERTS, DV;NICHOL, LW
通讯作者：
NICHOL, LW