Cellular-specific role of toll-like receptor 4 in hepatic ischemia-reperfusion injury in mice.
Cellular-specific role of toll-like receptor 4 in hepatic ischemia-reperfusion injury in mice.
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DOI：
10.1002/hep.26346
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发表时间：
2013-07
期刊：
影响因子：
13.5
通讯作者：
Tsung, Allan
中科院分区：
文献类型：
--
作者：
Nace, Gary W.;Huang, Hai;Klune, John R.;Eid, Raymond E.;Rosborough, Brian R.;Korff, Sebastian;Li, Shen;Shapiro, Richard A.;Stolz, Donna B.;Sodhi, Chhinder P.;Hackam, David J.;Geller, David A.;Billiar, Timothy R.;Tsung, Allan
缺血-再灌注（I/R）损伤是一个过程，其中初始缺氧损伤和随后的血流恢复导致先天性免疫应答和器官损伤的传播。模式识别受体Toll样受体（TLR）-4对于这种先天免疫应答的必要性先前已被证明。然而，TLR4存在于肝脏的各种细胞类型上，包括免疫细胞和非免疫细胞。因此，我们试图确定TLR4在单个细胞群中的作用，特别是肝实质肝细胞、髓样细胞（包括枯否细胞）和肝I/R后的树突状细胞。当肝细胞特异性（Alb-TLR4-/-）和骨髓细胞特异性（Lyz-TLR4-/-）TLR4敲除小鼠经受热肝缺血时，与野生型（WT）相比，在这些小鼠中存在显著保护。然而，在这两种品系中提供的保护显著低于整体TLR4特异性TLR4敲除（TLR4-/-）小鼠。与WT小鼠相比，树突状细胞特异性TLR4-/-（CD11c-TLR4-/-）小鼠具有显著增加的肝细胞损伤。与WT、Lyz-TLR 4-/-、CD11c-TLR 4-/-小鼠相比，Alb-TLR 4-/-小鼠的高迁移率族蛋白1（HMGB1）循环水平显著降低，与整体TLR 4-/-小鼠相当，表明TLR 4介导的HMGB1从肝细胞释放可能是I/R后HMGB1的来源。暴露于缺氧的肝细胞迅速磷酸化的丝裂原活化蛋白激酶JNK和p38的TLR4依赖性的方式作出反应，抑制JNK降低HMGB1的释放后，缺氧在体外和I/R在体内。这些结果提供了对TLR4的个体细胞应答的深入了解。研究发现，实质肝细胞是I/R后无菌炎症反应的积极参与者，通过TLR4介导的促炎信号转导激活和危险信号如HMGB1的释放。
Ischemia-reperfusion (I/R) injury is a process whereby an initial hypoxic insult and subsequent return of blood flow leads to the propagation of innate immune responses and organ injury. The necessity of the pattern recognition receptor, toll-like receptor (TLR)-4, for this innate immune response has been previously shown. However, TLR4 is present on various cell types of the liver, both immune and non-immune cells. Therefore, we sought to determine the role of TLR4 in individual cell populations, specifically parenchymal hepatocytes, myeloid cells including Kupffer cells, and dendritic cells following hepatic I/R. When hepatocyte specific (Alb-TLR4-/-) and myeloid cell specific (Lyz-TLR4-/-) TLR4 knockout mice were subjected to warm hepatic ischemia there was significant protection in these mice compared to wild-type (WT). However, the protection afforded in these two strains was significantly less than global TLR4 specific TLR4 knockout (TLR4-/-) mice. Dendritic cell specific TLR4-/- (CD11c-TLR4-/-) mice had significantly increased hepatocellular damage compared to WT mice. Circulating levels of high mobility group box-1 (HMGB1) were significantly reduced in the Alb-TLR4-/- mice compared to WT, Lyz-TLR4-/-, CD11c-TLR4-/- mice and equivalent to global TLR4-/- mice, suggesting that TLR4 mediated HMGB1 release from hepatocytes may be a source of HMGB1 after I/R. Hepatocytes exposed to hypoxia responded by rapidly phosphorylating the mitogen-activated protein kinases JNK and p38 in a TLR4-dependent manner; inhibition of JNK decreased the release of HMGB1 after both hypoxia in vitro and I/R in vivo. These results provide insight into the individual cellular response of TLR4. It was found that the parenchymal hepatocyte is an active participant in the sterile inflammatory response after I/R through TLR4-mediated activation of pro-inflammatory signaling and release of danger signals such as HMGB1.
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影响因子：
3.1
作者：
McCloskey, CA;Kameneva, MV;Billiar, TR
通讯作者：
Billiar, TR
影响因子：
4.6
作者：
Ellett, Justin D.;Atkinson, Carl;Evans, Zachary P.;Amani, Zainab;Balish, Edward;Schmidt, Michael G.;Schnellmann, Rick G.;Chavin, Kenneth D.
通讯作者：
Chavin, Kenneth D.
DOI：
10.1084/jem.20062648
发表时间：
2007-07-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Caton ML;Smith-Raska MR;Reizis B
通讯作者：
Reizis B
影响因子：
12.4
作者：
Devey, Luke;Ferenbach, David;Wigmore, Stephen J.
通讯作者：
Wigmore, Stephen J.
影响因子：
3
作者：
Clausen, BE;Burkhardt, C;Förster, I
通讯作者：
Förster, I