Cooperative interactions between TLR4 and TLR9 regulate interleukin 23 and 17 production in a murine model of gram negative bacterial pneumonia.
Cooperative interactions between TLR4 and TLR9 regulate interleukin 23 and 17 production in a murine model of gram negative bacterial pneumonia.
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DOI：
10.1371/journal.pone.0009896
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发表时间：
2010-03-26
期刊：
影响因子：
3.7
通讯作者：
Standiford TJ
中科院分区：
文献类型：
--
作者：
Bhan U;Ballinger MN;Zeng X;Newstead MJ;Cornicelli MD;Standiford TJ
Toll样受体在肺宿主对细菌病原体的防御中起重要作用。在这项研究中，我们研究了TLR4和TLR9在革兰氏阴性细菌性肺炎中微生物清除和全身传播中的独立和协同功能。为了获得这些反应，将野生型Balb/c小鼠、TLR4信号缺陷小鼠（TLR4lps-d）、TLR9缺陷小鼠（TLR9−/−）和TLR4/9双突变小鼠（TLR4lps-d/TLR9−/−）感染肺炎克雷伯菌，然后测定随时间变化的肺部细菌清除率和全身传播。我们发现TLR4和TLR9单突变小鼠肺部细菌清除率受损，而TLR4lps-d/TLR9−/−双突变小鼠肺部细菌清除率受损最大。TNF-α、IL-12和趋化因子的早期表达依赖于TLR4，而IFN-γ的产生和TNF-α、IL-12的晚期表达依赖于TLR9。肺巨噬细胞的经典活化和IL-23和IL-17的最大诱导需要TLR4和TLR9。最后，滴注IL-17可部分恢复TLR4lps-d/TLR9−/−双突变小鼠的抗菌免疫功能。综上所述，我们的研究表明，TLR4和TLR9在革兰氏阴性细菌性肺炎的肺先天反应中具有非冗余和协同的作用，并且都是IL-17驱动的抗菌宿主反应的关键。
Toll like receptors play an important role in lung host defense against bacterial pathogens. In this study, we investigated independent and cooperative functions of TLR4 and TLR9 in microbial clearance and systemic dissemination during Gram-negative bacterial pneumonia. To access these responses, wildtype Balb/c mice, mice with defective TLR4 signaling (TLR4lps-d), mice deficient in TLR9 (TLR9−/−) and TLR4/9 double mutant mice (TLR4lps-d/TLR9−/−) were challenged with K. pneumoniae, then time-dependent lung bacterial clearance and systemic dissemination determined. We found impaired lung bacterial clearance in TLR4 and TLR9 single mutant mice, whereas the greatest impairment in clearance was observed in TLR4lps-d/TLR9−/− double mutant mice. Early lung expression of TNF-α, IL-12, and chemokines was TLR4 dependent, while IFN-γ production and the later expression of TNF-α and IL-12 was dependent on TLR9. Classical activation of lung macrophages and maximal induction of IL-23 and IL-17 required both TLR4 and TLR9. Finally, the i.t. instillation of IL-17 partially restored anti-bacterial immunity in TLR4lps-d/TLR9−/− double mutant mice. In conclusion, our studies indicate that TLR4 and TLR9 have both non-redundant and cooperative roles in lung innate responses during Gram-negative bacterial pneumonia and are both critical for IL-17 driven antibacterial host response.
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影响因子：
15.9
作者：
Ito, Toshihiro;Schaller, Matthew;Kunkel, Steven L.
通讯作者：
Kunkel, Steven L.
影响因子：
3.1
作者：
Schurr, JR;Young, E;Kolls, JK
通讯作者：
Kolls, JK
影响因子：
3.7
作者：
Kannan S;Huang H;Seeger D;Audet A;Chen Y;Huang C;Gao H;Li S;Wu M
通讯作者：
Wu M
DOI：
10.1084/jem.20082767
发表时间：
2009-06-08
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Minegishi Y;Saito M;Nagasawa M;Takada H;Hara T;Tsuchiya S;Agematsu K;Yamada M;Kawamura N;Ariga T;Tsuge I;Karasuyama H
通讯作者：
Karasuyama H
影响因子：
4.4
作者：
Jeyaseelan, Samithamby;Young, Scott K.;Worthen, G. Scott
通讯作者：
Worthen, G. Scott