Toll-like receptor-4 coordinates the innate immune response of the kidney to renal ischemia/reperfusion injury.
Toll-like receptor-4 coordinates the innate immune response of the kidney to renal ischemia/reperfusion injury.
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TOLL样受体-4可以协调肾脏对肾脏缺血/再灌注损伤的先天免疫反应。
DOI：
10.1371/journal.pone.0003596
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Leemans, Jaklien C.
中科院分区：
文献类型：
--
作者：
Pulskens, Wilco P.;Teske, Gwendoline J.;Butter, Loes M.;Roelofs, Joris J.;van der Poll, Tom;Florquin, Sandrine;Leemans, Jaklien C.
Toll样受体（TLR）可以检测组织损伤后释放的内源性危险分子，导致诱导促炎反应。TLR家族成员之一的TLR 4在肾上皮细胞上以RNA水平组成性表达，并且这种表达在肾缺血/再灌注（I/R）损伤时增强。然而，这种器官特异性上调的功能相关性仍然未知。因此，我们研究了TLR 4的具体作用及其两个下游信号级联，MyD 88依赖性和TRIF依赖性级联在肾损伤中的相对贡献，通过使用TLR 4 −/−，MyD 88 −/−和TRIF突变小鼠进行肾缺血/再灌注损伤。我们的研究结果表明，TLR 4在I/R损伤时启动了一种夸张的促炎反应，这反映在与野生型小鼠相比，TLR 4 −/−小鼠的趋化因子和浸润性粒细胞水平较低，肾损伤较少，肾功能更好。体外研究表明，肾小管上皮细胞可以以TLR 4依赖性方式协调对缺血性损伤的免疫应答。在体内，我们发现，上皮细胞和白细胞相关的功能性TLR 4有助于在一个类似的比例肾功能不全和损伤的骨髓嵌合小鼠评估。令人惊讶的是，与野生型相比，MyD 88 −/−和TRIF突变小鼠的肾功能和炎症没有显著差异，这表明直接选择性靶向TLR 4可能比靶向TLR 4使用的细胞内途径更有效地用于开发预防I/R损伤的治疗工具。总之，我们确定TLR 4作为急性肾损伤的细胞哨兵，随后控制先天免疫应答的诱导。
Toll-like receptors (TLRs) can detect endogenous danger molecules released upon tissue injury resulting in the induction of a proinflammatory response. One of the TLR family members, TLR4, is constitutively expressed at RNA level on renal epithelium and this expression is enhanced upon renal ischemia/reperfusion (I/R) injury. The functional relevance of this organ-specific upregulation remains however unknown. We therefore investigated the specific role of TLR4 and the relative contribution of its two downstream signaling cascades, the MyD88-dependent and TRIF-dependent cascades in renal damage by using TLR4−/−, MyD88−/− and TRIF-mutant mice that were subjected to renal ischemia/reperfusion injury. Our results show that TLR4 initiates an exaggerated proinflammatory response upon I/R injury, as reflected by lower levels of chemokines and infiltrating granulocytes, less renal damage and a more preserved renal function in TLR4−/− mice as compared to wild type mice. In vitro studies demonstrate that renal tubular epithelial cells can coordinate an immune response to ischemic injury in a TLR4-dependent manner. In vivo we found that epithelial- and leukocyte-associated functional TLR4 contribute in a similar proportion to renal dysfunction and injury as assessed by bone marrow chimeric mice. Surprisingly, no significant differences were found in renal function and inflammation in MyD88−/− and TRIF-mutant mice compared with their wild types, suggesting that selective targeting of TLR4 directly may be more effective for the development of therapeutic tools to prevent I/R injury than targeting the intracellular pathways used by TLR4. In conclusion, we identified TLR4 as a cellular sentinel for acute renal damage that subsequently controls the induction of an innate immune response.
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DOI：
10.1073/pnas.0510041103
发表时间：
2006-04-18
影响因子：
11.1
作者：
Rowe, DC;McGettrick, AF;Golenbock, DT
通讯作者：
Golenbock, DT
影响因子：
4.4
作者：
Shigeoka, Alana A.;Holscher, Todd D.;McKay, Dianne B.
通讯作者：
McKay, Dianne B.
影响因子：
15.9
作者：
Leemans, JC;Stokman, G;Florquin, S
通讯作者：
Florquin, S
影响因子：
4.4
作者：
Cunningham, PN;Wang, Y;Quigg, RJ
通讯作者：
Quigg, RJ
影响因子：
15.9
作者：
Goldstein, DR;Tesar, BM;Lakkis, FG
通讯作者：
Lakkis, FG