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

Abstract

BackgroundDysfunctional 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).MethodsDNA 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.ResultsNo 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).ConclusionOur results demonstrate a notable association of TLR9(T1237C) expression with dysfunctional innate alveolar macrophage responses to respiratory pathogens and with severity of COPD.

Association between Toll-like receptor 9 gene polymorphisms and risk of bacterial meningitis in a Chinese population

“…The authors of a previous study reported that the TLR9 gene causes an intracellular receptor signal cascade, and thus evokes nuclear transcription factors resulting in the production of pro-and anti-inflammatory cytokines (Hemmi et al, 2000). The authors of previous studies have reported that TLR9 gene polymorphisms are associated with the development of several inflammatory diseases (Bharti et al, 2014;Berenson et al, 2015;Trejo-de la O et al, 2015;Wen et al, 2015;Wujcicka et al, 2015). Bharti et al (2014) conducted a study in a Chinese population and assessed the association between TLR9 polymorphisms and pulmonary tuberculosis; they found that the TLR9 rs187084 polymorphism was associated with reduced risk of pulmonary tuberculosis.…”

“…Wen et al (2015) reported that TLR9+2848 had a correlation with systemic lupus erythematosus in a Chinese population. Berenson et al (2015) indicated that TLR9-1237 expression was associated with the development and severity of chronic obstructive pulmonary disease. The studies mentioned above suggest that TLR9 gene polymorphisms are associated with inflammatory diseases.…”

The Toll-Like Receptors Role in Inflammatory Diseases of the Bronchopulmonary System Pathogenesis

“…Полиморфизм TLR2 (Arg32Gln) ассоцииру-ется с рецидивирующими инфекциями респира-торного тракта, полиморфизм TLR2 (Arg753Gln) сопровождается развитием стафилококкового сепсиса [29,30], полиморфизм TLR9 (T1237C) ассоциирован с повышенным риском развития бронхолегочного аспергиллеза, полиморфизм TLR1 (rs5743551) связывают с нарастанием случаев малярии в азиатской популяции [22]. Кроме того, интересной представляется четкая взаимосвязь наличия полиморфизма TLR9 (T1237C) с рос-том случаев бронхиальной астмы в европейс-кой популяции [16]. Наряду с представленными данными есть исследования, не обнаружившие связи полиморфизма и/или мутаций в TLR4 (Asp299Gly) и TLR2 (Arg753Gln) и увеличением частоты развития инфекций [34,35,36,40].…”

Lessons of microbiota

“…Изучается роль ТПР при пневмониях [13], ХОЗЛ [22], туберкулёзе [3], аутоиммунных болезнях, злокачественных опухолях [34], болезнях почек [17], ТПР обнаружены на эпителиоцитах верхних дыхательных путей [5]. Высказывается мнение, что развитие инфекционных, аутоиммунных, иммунокомплексных болезней возможно только при наличии дефекта ТПР на уровне самих рецепторов, различий сигналов на уровне факторов, регулирующих функции ТПР.…”