TLR9 expression is required for the development of cigarette smoke-induced emphysema in mice
TLR9 expression is required for the development of cigarette smoke-induced emphysema in mice
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DOI：
10.1152/ajplung.00073.2016
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发表时间：
2016-07-01
影响因子：
4.9
通讯作者：
Geraghty, Patrick
中科院分区：
文献类型：
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作者：
Foronjy, Robert F.;Salathe, Matthias A.;Geraghty, Patrick
TLR 9表达是香烟烟雾诱导的小鼠肺气肿发展所必需的。美国生理学杂志肺细胞分子生理学311：L154-L166，2016。首次发表于2016年6月10日; doi：10.1152/ajplung.00073.2016.- Toll样受体（TLR）-9是一种识别微生物DNA分子中未甲基化CpG序列的病原体识别受体，其表达与几种肺部疾病的发病机制有关。在慢性阻塞性肺疾病（COPD）的动物和细胞模型中研究TLR 9表达和信号传导。我们观察到暴露于香烟烟雾后小鼠肺中TLR 9表达增强。通过平均线性截距、总肺容量、肺顺应性和组织弹性分析确定，Tlr 9（-/-）小鼠对香烟烟雾诱导的肺功能丧失具有抗性。Tlr 9表达还调节烟雾介导的免疫细胞向肺的募集;细胞凋亡;粒细胞集落刺激因子（G-CSF）、CXCL 5蛋白和基质金属蛋白酶-2（MMP-2）的表达;以及肺中蛋白酪氨酸磷酸酶1B（PTP 1B）的活性。PTP 1B是一种具有抗炎能力的磷酸酶，被鉴定为与TLR 9结合。TLR 9激动剂的体内递送增强了TLR 9与PTP 1B的结合，这使PTP 1B失活。与野生型小鼠相比，Ptp 1b（-/-）小鼠在TLR 9激动剂给药后，G-CSF、CXCL 5和MMP-2的肺浓度升高，1型干扰素的组织表达升高。TLR 9应答在从非吸烟者、吸烟者和COPD供体分离的完全分化的正常人支气管上皮（NHBE）细胞中进一步测定，然后在气液界面培养。与来自非吸烟者供体的细胞相比，来自吸烟者和COPD患者的NHBE细胞表达更多的TLR 9，并且在TLR 9配体刺激后分泌更高水平的G-CSF、IL-6、CXCL 5、IL-1 β和MMP-2。尽管TLR 9可以对抗感染，但我们的研究结果表明TLR 9诱导可以通过灭活PTP 1B和上调促炎细胞因子的表达来影响肺功能。
TLR9 expression is required for the development of cigarette smoke-induced emphysema in mice. Am J Physiol Lung Cell Mol Physiol 311:L154-L166, 2016. First published June 10, 2016; doi:10.1152/ajplung.00073.2016.-The expression of Toll-like receptor (TLR)-9, a pathogen recognition receptor that recognizes unmethylated CpG sequences in microbial DNA molecules, is linked to the pathogenesis of several lung diseases. TLR9 expression and signaling was investigated in animal and cell models of chronic obstructive pulmonary disease (COPD). We observed enhanced TLR9 expression in mouse lungs following exposure to cigarette smoke. Tlr9(-/-) mice were resistant to cigarette smoke-induced loss of lung function as determined by mean linear intercept, total lung capacity, lung compliance, and tissue elastance analysis. Tlr9 expression also regulated smoke-mediated immune cell recruitment to the lung; apoptosis; expression of granulocyte-colony stimulating factor (G-CSF), the CXCL5 protein, and matrix metalloproteinase-2 (MMP-2); and protein tyrosine phosphatase 1B (PTP1B) activity in the lung. PTP1B, a phosphatase with anti-inflammatory abilities, was identified as binding to TLR9. In vivo delivery of a TLR9 agonist enhanced TLR9 binding to PTP1B, which inactivated PTP1B. Ptp1b(-/-) mice had elevated lung concentrations of G-CSF, CXCL5, and MMP-2, and tissue expression of type-1 interferon following TLR9 agonist administration, compared with wild-type mice. TLR9 responses were further determined in fully differentiated normal human bronchial epithelial (NHBE) cells isolated from nonsmoker, smoker, and COPD donors, and then cultured at air liquid interface. NHBE cells from smokers and patients with COPD expressed more TLR9 and secreted greater levels of G-CSF, IL-6, CXCL5, IL-1 beta, and MMP-2 upon TLR9 ligand stimulation compared with cells from nonsmoker donors. Although TLR9 combats infection, our results indicate that TLR9 induction can affect lung function by inactivating PTP1B and upregulating expression of proinflammatory cytokines.