Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney
Renal-associated TLR2 mediates ischemia/reperfusion injury in the kidney
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DOI：
10.1172/jci22832
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发表时间：
2005-10-01
影响因子：
15.9
通讯作者：
Florquin, S
中科院分区：
文献类型：
--
作者：
Leemans, JC;Stokman, G;Florquin, S
Toll样受体（TLRs）是保守的模式识别受体，可检测病原体的特定结构以及损伤过程中释放的宿主物质。由于未知原因，肾脏Toll样受体2（TLR2）的信使核糖核酸（mRNA）主要由肾小管细胞表达，并且在肾脏缺血/再灌注（I/R）损伤时表达增强。我们利用TLR2基因敲除（-/-）和野生型（+/+）小鼠、TLR2反义寡核苷酸以及白细胞或肾脏TLR2缺陷的嵌合小鼠，评估了TLR2在缺血/再灌注损伤中的作用。在体外缺血条件下，肾小管细胞需要TLR2来产生大量细胞因子和趋化因子。在体内缺血/再灌注损伤后，TLR2发挥促炎和有害作用，这体现在与对照组相比，TLR2基因敲除小鼠局部细胞因子和趋化因子的量、白细胞数量以及肾脏损伤和功能障碍的程度均降低。对嵌合小鼠的分析表明，肾实质表达的TLR2在炎症和损伤的诱导中起关键作用。与无义处理相比，TLR2反义处理可保护小鼠免受缺血/再灌注损伤后的肾功能障碍、中性粒细胞浸润和肾小管细胞凋亡。总之，我们确定肾脏相关的TLR2是缺血/再灌注损伤中导致肾脏损伤和功能障碍的炎症反应的重要起始因子。这些数据表明，阻断TLR2可为治疗或预防肾脏缺血性损伤的治疗策略提供依据。
TLRs are conserved pattern recognition receptors that detect motifs of pathogens and host material released during injury. For unknown reasons, renal TLR2 mRNA is mainly expressed by tubular cells and is enhanced upon renal ischemia/reperfusion (I/R) injury. We evaluated the role of TLR2 in I/R injury using TLR2(-/-) and TLR2(+/+) mice, TLR2 antisense oligonucleoddes, and chimeric mice deficient in leukocyte or renal TLR2. Tubular-cells needed TLR2 to produce significant cytokine and chemokine amounts upon ischemia in vitro. TLR2 played a proinflammatory and detrimental role in vivo after I/R injury, as reflected by a reduction in the amount of local cytokines and chemokines, leukocytes, and the level of renal injury and dysfucntion in TLR2(-/-) mice compared with controls. Analysis of chimeric mice suggested that TLR2 expressed on renal parenchyma plays a crucial role in the induction of inflammation and injury. TLR2-antisense treatment protected mice from renal dysfunction, neutrophil influx, and tubular apoptosis after I/R injury compared with nonsense treatment. In summary, we identified renal-associated TLR2 as an important initiator of inflammatory responses leading to renal injury and dysfunction in I/R injury. These data imply that TLR2 blockade could provide a basis for therapeutic strategies to treat or prevent renal ischemic injury.