Toll-like receptor 9 inhibition confers protection from liver ischemia-reperfusion injury.
Toll-like receptor 9 inhibition confers protection from liver ischemia-reperfusion injury.
复制标题
DOI：
10.1002/hep.23365
复制
发表时间：
2010-02
期刊：
影响因子：
13.5
通讯作者：
DeMatteo, Ronald P.
中科院分区：
文献类型：
--
作者：
Bamboat, Zubin M.;Balachandran, Vinod P.;Ocuin, Lee M.;Obaid, Hebroon;Plitas, George;DeMatteo, Ronald P.
内源性配体如高迁移率族蛋白1（HMGB 1）和核酸由死亡细胞释放并结合Toll样受体（TLR）。由于TLR 9通过检测细菌和内源性DNA位于微生物和无菌炎症的界面，我们研究了其在节段性肝缺血再灌注（I/R）损伤模型中的作用。在评估肝损伤、细胞因子和活性氧（ROS）之前，使小鼠经受1小时的缺血和12小时的再灌注。用抑制性CpG（iCpG）序列处理的野生型（WT）小鼠和TLR 9 −/−小鼠在肝脏I/R后血清丙氨酸氨基转移酶（ALT）和炎性细胞因子显著降低。肝损伤由骨髓来源的细胞介导，因为移植TLR 9 −/−骨髓的WT小鼠免受肝I/R损伤。WT小鼠的损伤部分依赖于中性粒细胞中的TLR 9信号传导，其增强ROS、IL-6和TNF的产生。在体外，从坏死肝细胞释放的DNA通过TLR 9依赖性机制增加肝非实质细胞（NPC）和中性粒细胞的细胞因子分泌。TLR 9和HMGB 1的抑制引起中性粒细胞培养物中最大的炎性细胞因子抑制，并赋予体内I/R损伤更大的保护作用。TLR 9作为组织坏死的内源性传感器，在肝脏I/R期间加剧先天性免疫应答。TLR 9和HMGB 1的联合阻断代表了限制I/R损伤的临床相关的新方法。
Endogenous ligands such as high-mobility group box 1 (HMGB1) and nucleic acids are released by dying cells and bind Toll-like receptors (TLRs). Because TLR9 sits at the interface of microbial and sterile inflammation by detecting both bacterial and endogenous DNA, we investigated its role in a model of segmental liver ischemia-reperfusion (I/R) injury. Mice were subjected to 1 h of ischemia and 12 h of reperfusion prior to assessment of liver injury, cytokines and reactive oxygen species (ROS). Wild-type (WT) mice treated with an inhibitory CpG (iCpG) sequence and TLR9−/− mice had markedly reduced serum alanine aminotransferase (ALT) and inflammatory cytokines following liver I/R. Liver damage was mediated by bone marrow derived cells as WT mice transplanted with TLR9−/− bone marrow were protected from hepatic I/R injury. Injury in WT mice partly depended on TLR9 signaling in neutrophils, which enhanced production of ROS, IL-6, and TNF. In vitro, DNA released from necrotic hepatocytes increased liver non-parenchymal cell (NPC) and neutrophil cytokine secretion via a TLR9-dependent mechanism. Inhibition of both TLR9 and HMGB1 caused maximal inflammatory cytokine suppression in neutrophil cultures and conferred even greater protection from I/R injury in vivo. TLR9 serves as an endogenous sensor of tissue necrosis that exacerbates the innate immune response during liver I/R. Combined blockade of TLR9 and HMGB1 represents a clinically relevant, novel approach to limiting I/R injury.
登录
查看更多内容
影响因子：
12.4
作者：
Cerullo, Vincenzo;Seiler, Michael P.;Lee, Brendan
通讯作者：
Lee, Brendan
DOI：
10.1126/science.1168988
发表时间：
2009-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Chen GY;Tang J;Zheng P;Liu Y
通讯作者：
Liu Y
影响因子：
15.9
作者：
COLLETTI, LM;REMICK, DG;CAMPBELL, DA
通讯作者：
CAMPBELL, DA
影响因子：
6
作者：
Kato, A;Gabay, C;Lentsch, AB
通讯作者：
Lentsch, AB
影响因子：
4.4
作者：
Katz, SC;Pillarisetty, VG;DeMatteo, RP
通讯作者：
DeMatteo, RP