Related Experiment Video
Updated: Apr 4, 2026
In Vivo Assessment of Alveolar Macrophage Efferocytosis Following Ozone Exposure
Published on: October 22, 2019
Impaired Innate COPD Alveolar Macrophage Responses and Toll-Like Receptor-9 Polymorphisms
Charles S Berenson1, Ragina L Kruzel1, Catherine T Wrona2
1Division of Infectious Diseases, Department of Veterans Affairs Western New York Healthcare System, State University of New York at Buffalo School of Medicine, Buffalo, New York, 14215, United States of America.
Background:
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).
Methods:
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.
Results:
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).
Conclusion:
Our results demonstrate a notable association of TLR9(T1237C) expression with dysfunctional innate alveolar macrophage responses to respiratory pathogens and with severity of COPD.
Insights
Specific Toll-like receptor 9 (TLR9) polymorphisms are linked to impaired immune responses in chronic obstructive pulmonary disease (COPD) patients. This TLR9(T1237C) variant is associated with reduced macrophage function and disease severity in COPD.
Area of Science:
- Immunology
- Pulmonology
- Genetics
Background:
- Dysfunctional innate immune responses in alveolar macrophages contribute to chronic obstructive pulmonary disease (COPD) morbidity.
- Impaired macrophage responses to Toll-like receptor (TLR) ligands in COPD warrant further investigation of TLR signaling.
- Single nucleotide polymorphisms (SNPs) in TLRs are increasingly recognized in inflammatory diseases, with recent exploration in COPD.
Purpose of the Study:
- To investigate the association between specific TLR polymorphisms (TLR2, TLR4, TLR9) and dysfunctional innate immune responses in COPD alveolar macrophages.
- To determine if TLR polymorphisms correlate with COPD severity and impaired responses to common respiratory pathogens.
Main Methods:
- DNA was purified from healthy nonsmokers, COPD ex-smokers, and COPD active smokers.
- Polymerase chain reaction was used to amplify specific single nucleotide polymorphisms (SNPs) in TLR2, TLR4, and TLR9.
- Alveolar macrophages were incubated with nontypeable H. influenzae, M. catarrhalis, and S. pneumoniae to measure cytokine induction and assess association with TLR SNP expression.
Main Results:
- No significant inter-group differences in the frequency of any tested TLR SNP were found.
- Both TLR9 single nucleotide polymorphisms (SNPs) were expressed at high frequencies.
- Among COPD ex-smokers, diminished IL-8 responsiveness to respiratory pathogens was strongly associated with TLR9(T1237C) carriage (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).
Conclusions:
- TLR9(T1237C) expression is notably associated with dysfunctional innate alveolar macrophage responses to key respiratory pathogens.
- The TLR9(T1237C) polymorphism is linked to increased severity of chronic obstructive pulmonary disease (COPD).
More Related Videos
Related Concept Videos
01:20Chronic Obstructive Pulmonary Disease-II: Pathophysiology
Chronic Inflammation
01:20COPD: Pathogenesis and Clinical Features
The primary cause for the onset of COPD is cigarette smoking and exposure to air pollution. These hazardous factors initiate a chain reaction within the lungs, resulting in chronic inflammation, damage to the airways, and a...
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase
01:29Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
01:20Chronic Obstructive Pulmonary Disease-I: Introduction