Impaired Innate COPD Alveolar Macrophage Responses and Toll-Like Receptor-9 Polymorphisms

<div><p>Background</p><p>Dysfunctional innate responses of alveolar macrophages to nontypeable <i>Haemophilus influenzae</i>, <i>Moraxella catarrhalis</i> and <i>Streptococcus pneumoniae</i> 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 <i>H</i>. <i>influenzae</i> 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).</p><p>Methods</p><p>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 <i>H</i>. <i>influenzae</i>, <i>M</i>. <i>catarrhalis</i> and <i>S</i>. <i>pneumoniae</i>. Cytokine induction of macrophage supernatants was measured and the association with TLR single nucleotide polymorphism expression was determined.</p><p>Results</p><p>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 <i>H</i>. <i>influenzae</i>, <i>M</i>. <i>catarrhalis</i> and <i>S</i>. <i>pneumoniae</i> 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 FEV<sub>1</sub>%predicted (p = 0.037).</p><p>Conclusion</p><p>Our results demonstrate a notable association of TLR9(T1237C) expression with dysfunctional innate alveolar macrophage responses to respiratory pathogens and with severity of COPD.</p></div>