Opsonic phagocytosis in chronic obstructive pulmonary disease is enhanced by Nrf2 agonists
File(s)
Accepted version
Accepted version
Author(s)
Type
Journal Article
Abstract
Rationale: Previous studies have identified defects in bacterial phagocytosis by alveolar macrophages (AM) in patients with chronic obstructive pulmonary disease (COPD) but the mechanisms and clinical consequences remain incompletely defined.
Objectives: To examine the effect of COPD on AM phagocytic responses and identify the mechanisms, clinical consequences and potential for therapeutic manipulation of these defects.
Methods: We isolated alveolar macrophages (AM) and monocyte-derived macrophages (MDM) from a cohort of COPD patients and controls within the MRC COPD-MAP consortium and measured phagocytosis of bacteria in relation to opsonic conditions and clinical features.
Measurements and Main Results: COPD AM and MDM have impaired phagocytosis of S. pneumoniae. COPD AM have a selective defect in uptake of opsonized bacteria, despite the presence of anti-pneumococcal antibodies in bronchoalveolar lavage, not observed in MDM or healthy donor’s AM. AM defects in phagocytosis in COPD are significantly associated with exacerbation frequency, isolation of pathogenic bacteria and health related quality of life scores. Bacterial binding and initial intracellular killing of opsonized bacteria in COPD AM was not reduced. COPD AM have reduced transcriptional responses to opsonized bacteria, including cellular stress responses that include transcriptional modules involving antioxidant defenses and Nrf2-regualted genes. Agonists of the cytoprotective transcription factor Nrf2 (sulforaphane and Compound 7) reverse defects in phagocytosis of S. pneumoniae and non-type able Haemophilus influenzae by COPD AM.
Conclusions: Patients with COPD have clinically relevant defects in opsonic phagocytosis by AM, associated with impaired transcriptional responses to cellular stress, which are reversed by therapeutic targeting with Nrf2 agonists.
Objectives: To examine the effect of COPD on AM phagocytic responses and identify the mechanisms, clinical consequences and potential for therapeutic manipulation of these defects.
Methods: We isolated alveolar macrophages (AM) and monocyte-derived macrophages (MDM) from a cohort of COPD patients and controls within the MRC COPD-MAP consortium and measured phagocytosis of bacteria in relation to opsonic conditions and clinical features.
Measurements and Main Results: COPD AM and MDM have impaired phagocytosis of S. pneumoniae. COPD AM have a selective defect in uptake of opsonized bacteria, despite the presence of anti-pneumococcal antibodies in bronchoalveolar lavage, not observed in MDM or healthy donor’s AM. AM defects in phagocytosis in COPD are significantly associated with exacerbation frequency, isolation of pathogenic bacteria and health related quality of life scores. Bacterial binding and initial intracellular killing of opsonized bacteria in COPD AM was not reduced. COPD AM have reduced transcriptional responses to opsonized bacteria, including cellular stress responses that include transcriptional modules involving antioxidant defenses and Nrf2-regualted genes. Agonists of the cytoprotective transcription factor Nrf2 (sulforaphane and Compound 7) reverse defects in phagocytosis of S. pneumoniae and non-type able Haemophilus influenzae by COPD AM.
Conclusions: Patients with COPD have clinically relevant defects in opsonic phagocytosis by AM, associated with impaired transcriptional responses to cellular stress, which are reversed by therapeutic targeting with Nrf2 agonists.
Date Issued
2018-09-15
Date Acceptance
2018-02-24
Citation
American Journal of Respiratory and Critical Care Medicine, 2018, 198 (6), pp.739-750
ISSN
1073-449X
Publisher
American Thoracic Society
Start Page
739
End Page
750
Journal / Book Title
American Journal of Respiratory and Critical Care Medicine
Volume
198
Issue
6
Copyright Statement
© 2018 by the American Thoracic Society
Sponsor
Medical Research Council (MRC)
Grant Number
G1001372
Subjects
Science & Technology
Life Sciences & Biomedicine
Critical Care Medicine
Respiratory System
General & Internal Medicine
chronic obstructive pulmonary disease
macrophage
phagocytosis
antioxidant
nuclear factor erythroid 2-related factor 2 (Nrf2)
COMMUNITY-ACQUIRED PNEUMONIA
HUMAN ALVEOLAR MACROPHAGES
STREPTOCOCCUS-PNEUMONIAE
PNEUMOCOCCAL INFECTION
MEDIATED PHAGOCYTOSIS
COPD EXACERBATIONS
LUNG-DISEASE
CYCLIC-AMP
BACTERIA
SUSCEPTIBILITY
nuclear factor erythroid 2–related factor 2 (Nrf2)
COPDMAP
11 Medical And Health Sciences
Publication Status
Published
Date Publish Online
2018-03-16