Impaired Innate COPD Alveolar Macrophage Responses and Toll-Like Receptor-9 Polymorphisms.
Impaired Innate COPD Alveolar Macrophage Responses and Toll-Like Receptor-9 Polymorphisms.
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DOI：
10.1371/journal.pone.0134209
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Sethi S
中科院分区：
文献类型：
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作者：
Berenson CS;Kruzel RL;Wrona CT;Mammen MJ;Sethi S
肺泡巨噬细胞对非分型流感嗜血杆菌、卡他莫拉菌和肺炎链球菌的先天功能障碍导致慢性阻塞性肺疾病(COPD)的发病。我们早期的研究发现COPD肺泡巨噬细胞对非分型流感嗜血杆菌的Toll样受体(TLR)配体的反应受损，并为进一步评估TLR信号提供了理论基础。虽然TLR单核苷酸多态在炎症性疾病中的作用越来越被认识，但在COPD中TLR单核苷酸多态直到最近才被探索。我们假设特定的TLR基因多态与先天性免疫性COPD肺泡巨噬细胞功能障碍相关，并研究了TLR2(Arg753Gln)、TLR4(Thr399Ile；Asp299Gly)和TLR9(T1486C；T1237C)的多态。从健康非吸烟者(n=20)、COPD既往吸烟者(n=83)、COPD活动期吸烟者(n=93)的细胞中提取DNA。对每个SNP进行DNA扩增(聚合酶链式反应)。各组肺泡巨噬细胞分别与非分型流感嗜血杆菌、卡他分支杆菌和肺炎链球菌共同孵育。检测巨噬细胞培养上清液中细胞因子的诱导作用，并分析其与TLR单核苷酸多态表达的关系。任何TLR SNP的频率在组内不存在显著差异。而TLR9两个单核苷酸多态的表达频率均较高。在COPD既往吸烟者中，IL-8对非分型流感嗜血杆菌、卡他分支杆菌和肺炎链球菌的反应性降低与携带TLR9(T1237C)密切相关(p=0.02；p=0.008；p=0.02)，但与TLR9(T1486C)无关。TLR9(T1237C)携带者，而TLR9(T1486C)携带者，与预计FEV1%下降相关(P=0.037)。我们的结果表明，TLR9(T1237C)的表达与先天性肺泡巨噬细胞对呼吸道病原体的功能障碍以及与COPD的严重程度有显著的相关性。
Dysfunctional innate responses of alveolar macrophages to nontypeable Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae contribute to morbidity in chronic obstructive pulmonary disease (COPD). Our earlier studies discovered impaired COPD alveolar macrophage responses to Toll-like receptor (TLR) ligands of nontypeable H. influenzae and provide rationale for further evaluation of TLR signaling. While the role of TLR single nucleotide polymorphisms is increasingly recognized in inflammatory diseases, TLR single nucleotide polymorphisms in COPD have only recently been explored. We hypothesized that specific TLR polymorphisms are associated with dysfunctional innate immune COPD alveolar macrophage responses and investigated polymorphisms of TLR2(Arg753Gln), TLR4(Thr399Ile; Asp299Gly), and TLR9(T1486C; T1237C). DNA was purified from cells of 1) healthy nonsmokers (n = 20); 2) COPD ex-smokers (n = 83); 3) COPD active smokers (n = 93). DNA amplifications (polymerase chain reaction) were performed for each SNP. Alveolar macrophages from each group were incubated with nontypeable H. influenzae, M. catarrhalis and S. pneumoniae. Cytokine induction of macrophage supernatants was measured and the association with TLR single nucleotide polymorphism expression was determined. No significant inter-group differences in frequency of any TLR SNP existed. However both TLR9 single nucleotide polymorphisms were expressed in high frequency. Among COPD ex-smokers, diminished IL-8 responsiveness to nontypeable H. influenzae, M. catarrhalis and S. pneumoniae was strongly associated with carriage of TLR9(T1237C) (p = 0.02; p = 0.008; p = 0.02), but not TLR9(T1486C). Carriage of TLR9(T1237C), but not TLR9(T1486C), correlated with diminished FEV1%predicted (p = 0.037). Our results demonstrate a notable association of TLR9(T1237C) expression with dysfunctional innate alveolar macrophage responses to respiratory pathogens and with severity of COPD.