Central role of toll-like receptor 4 signaling and host defense in experimental pneumonia caused by gram-negative bacteria
Central role of toll-like receptor 4 signaling and host defense in experimental pneumonia caused by gram-negative bacteria
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DOI：
10.1128/iai.73.1.532-545.2005
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发表时间：
2005-01-01
影响因子：
3.1
通讯作者：
Kolls, JK
中科院分区：
文献类型：
--
作者：
Schurr, JR;Young, E;Kolls, JK
Toll样受体4（TLR 4）已被鉴定为脂多糖的受体。然而，TLR 4在革兰氏阴性菌感染后调节基因表达的确切作用尚未完全阐明。通过在具有低剂量肺炎克雷伯氏菌感染的实验性肺炎小鼠模型中肺组织中的基因表达谱来评估TLR 4信号传导在协调基因表达中的作用。我们分析了四种小鼠品系：C57 BL/6小鼠，其对细菌传播具有抗性; 129/SvJ小鼠，其是易感的; C3 H/HeJ小鼠，其是易感的并且具有缺陷的TLR 4信号传导;以及它们各自的对照品系，C3 H/HeN（中等抗性）。在感染后4 h，C57 BL/6和C3 H/HeN小鼠表现出最多的基因，具有67个共享的诱导基因，这些基因是TLR 4依赖的并且与抗性表型高度相关。这些基因包括中性粒细胞活化或募集所需的细胞因子和趋化因子基因、生长因子受体、MyD 88（TLR信号传导的关键衔接蛋白）和粘附分子。TLR 4信号转导占C3 H背景下基因表达的74%以上。这些数据表明，早期TLR 4信号控制了肺中绝大多数基因表达，以响应革兰氏阴性菌引起的感染，并且随后的基因表达决定了宿主的存活。
Toll-like receptor 4 (TLR4) has been identified as a receptor for lipopolysaccharide. However, the precise role of TLR4 in regulating gene expression in response to an infection caused by gram-negative bacteria has not been fully elucidated. The role of TLR4 signaling in coordinating gene expression was assessed by gene expression profiling in lung tissue in a mouse model of experimental pneumonia with a low-dose infection of Klebsiella pneumoniae. We analyzed four mouse strains: C57BL/6 mice, which are resistant to bacterial dissemination; 129/SvJ mice, which are susceptible; C3H/HeJ mice, which are susceptible and have defective TLR4 signaling; and their respective control strain, C3H/HeN (intermediate resistance). At 4 h after infection, C57BL/6 and C3H/HeN mice demonstrated the greatest number of genes, with 67 shared induced genes which were TLR4 dependent and highly associated with the resistance phenotype. These genes included cytokine and chemokine genes required for neutrophil activation or recruitment, growth factor receptors, MyD88 (a critical adaptor protein for TLR signaling), and adhesion molecules. TLR4 signaling accounted for over 74% of the gene expression in the C3H background. These data suggest that early TLR4 signaling controls the vast majority of gene expression in the lung in response to an infection caused by gram-negative bacteria and that this subsequent gene expression determines survival of the host.