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In Vivo Assessment of Alveolar Macrophage Efferocytosis Following Ozone Exposure
Published on: October 22, 2019
Impaired innate immune alveolar macrophage response and the predilection for COPD exacerbations
Charles S Berenson1, Ragina L Kruzel1, Ellana Eberhardt2
1Infectious Disease Division, Department of Veterans Affairs Western New York Healthcare System, State University of New York at Buffalo School of Medicine, Buffalo, New York, USA.
Background:
Alveolar macrophages (AM) in COPD have fundamentally impaired responsiveness to Toll-like receptor 2 (TLR2) and TLR4 ligands of non-typeable Haemophilus influenzae (NTHI). However, the contribution of innate immune dysfunction to exacerbations of COPD is unexplored. We hypothesised that impaired innate AM responses in COPD extend beyond NTHI to other pathogens and are linked with COPD exacerbations and severity.
Methods:
AMs, obtained by bronchoalveolar lavage from 88 volunteers with stable-to-moderate COPD, were incubated with respiratory pathogens (NTHI, Moraxella catarrhalis (MC), Streptococcus pneumoniae (SP) and TLR ligands lipopolysaccharide, Pam3Cys) and elicited IL-8 and TNF-α were measured by microsphere flow cytometry. NF-κB nuclear translocation was measured by colorimetric assay. AM TLR2 and TLR4 expression was determined by immunolabeling and quantitation of mean fluorescent indices. Participants were monitored prospectively for occurrence of COPD exacerbations for 1 year following bronchoscopy. Non-parametric analyses were used to compare exacerbation-prone and non-exacerbation-prone individuals.
Results:
29 subjects had at least one exacerbation in the follow-up period (exacerbation-prone) and 59 remained exacerbation-free (non-exacerbation-prone). AMs of exacerbation-prone COPD donors were more refractory to cytokine induction by NTHI (p=0.02), MC (p=0.045) and SP (p=0.046), and to TLR2 (p=0.07) and TLR4 (p=0.028) ligands, and had diminished NF-κB nuclear activation, compared with non-exacerbation-prone counterparts. AMs of exacerbation-prone subjects were more refractory to TLR2 upregulation by MC and SP (p=0.04 each).
Conclusions:
Our results support a paradigm of impaired innate responses of COPD AMs to respiratory pathogens, mediated by impaired TLR responses, underlying a propensity for exacerbations in COPD.
Insights
In Chronic Obstructive Pulmonary Disease (COPD), impaired alveolar macrophage (AM) responses to pathogens, particularly via Toll-like receptor (TLR) pathways, are linked to increased exacerbations. This study reveals dysfunctional innate immunity in COPD exacerbation-prone individuals.
Area of Science:
- Immunology
- Pulmonology
- Infectious Disease
Background:
- Alveolar macrophages (AMs) in Chronic Obstructive Pulmonary Disease (COPD) exhibit impaired responses to Toll-like receptor 2 (TLR2) and TLR4 ligands from non-typeable Haemophilus influenzae (NTHI).
- The role of innate immune dysfunction in COPD exacerbations remains largely unexplored.
- This study hypothesizes that impaired innate AM responses in COPD extend to other pathogens and correlate with exacerbation frequency and disease severity.
Purpose of the Study:
- To investigate the innate immune response of AMs from COPD patients to various respiratory pathogens and TLR ligands.
- To determine if impaired AM responses are associated with a propensity for COPD exacerbations.
- To explore the link between AM dysfunction, TLR signaling, and COPD exacerbation risk.
Main Methods:
- Bronchoalveolar lavage (BAL) was performed on 88 stable-to-moderate COPD volunteers.
- AMs were stimulated with respiratory pathogens (NTHI, Moraxella catarrhalis, Streptococcus pneumoniae) and TLR ligands (lipopolysaccharide, Pam3Cys).
- Cytokine (IL-8, TNF-α) production, NF-κB activation, and AM TLR expression were measured. Participants were prospectively monitored for exacerbations over one year.
Main Results:
- Exacerbation-prone individuals (29/88) showed significantly more refractory AMs to cytokine induction by NTHI, MC, and SP compared to exacerbation-free individuals (59/88).
- Impaired NF-κB nuclear translocation and diminished TLR2/TLR4 upregulation on AMs were observed in exacerbation-prone COPD donors.
- Refractory responses to TLR2 and TLR4 ligands were more pronounced in AMs from exacerbation-prone COPD patients.
Conclusions:
- The findings support a paradigm of impaired innate immune responses in COPD AMs to common respiratory pathogens.
- Dysfunctional Toll-like receptor (TLR) signaling in AMs contributes to the propensity for exacerbations in COPD.
- Targeting innate immune dysfunction in AMs may offer therapeutic strategies for reducing COPD exacerbations.
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