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Published on: October 22, 2019
Impaired Mitochondrial Microbicidal Responses in Chronic Obstructive Pulmonary Disease Macrophages
Martin A Bewley1,2, Julie A Preston1,2, Mohammed Mohasin1,2
11 The Florey Institute for Host-Pathogen Interactions and.
Rationale:
Chronic obstructive pulmonary disease (COPD) is characterized by impaired clearance of pulmonary bacteria.
Objectives:
The effect of COPD on alveolar macrophage (AM) microbicidal responses was investigated.
Methods:
AMs were obtained from bronchoalveolar lavage from healthy donors or patients with COPD and challenged with opsonized serotype 14 Streptococcus pneumoniae. Cells were assessed for apoptosis, bactericidal activity, and mitochondrial reactive oxygen species (mROS) production. A transgenic mouse line in which the CD68 promoter ensures macrophage-specific expression of human induced myeloid leukemia cell differentiation protein Mcl-1 (CD68.hMcl-1) was used to model the molecular aspects of COPD.
Measurements And Main Results:
COPD AMs had elevated levels of Mcl-1, an antiapoptotic B-cell lymphoma 2 family member, with selective reduction of delayed intracellular bacterial killing. CD68.hMcl-1 AMs phenocopied the microbicidal defect because transgenic mice demonstrated impaired clearance of pulmonary bacteria and increased neutrophilic inflammation. Murine bone marrow-derived macrophages and human monocyte-derived macrophages generated mROS in response to pneumococci, which colocalized with bacteria and phagolysosomes to enhance bacterial killing. The Mcl-1 transgene increased oxygen consumption rates and mROS expression in mock-infected bone marrow-derived macrophages but reduced caspase-dependent mROS production after pneumococcal challenge. COPD AMs also increased basal mROS expression, but they failed to increase production after pneumococcal challenge, in keeping with reduced intracellular bacterial killing. The defect in COPD AM intracellular killing was associated with a reduced ratio of mROS/superoxide dismutase 2.
Conclusions:
Up-regulation of Mcl-1 and chronic adaption to oxidative stress alter mitochondrial metabolism and microbicidal function, reducing the delayed phase of intracellular bacterial clearance in COPD.
Insights
Chronic obstructive pulmonary disease (COPD) impairs bacterial clearance due to altered macrophage function. Increased Mcl-1 in COPD macrophages reduces their ability to kill bacteria, impacting lung health.
Area of Science:
- Immunology
- Pulmonology
- Cell Biology
Background:
- Chronic obstructive pulmonary disease (COPD) is associated with compromised pulmonary bacterial clearance.
- Alveolar macrophages (AMs) play a crucial role in lung defense against bacterial infections.
Purpose of the Study:
- To investigate the impact of COPD on the microbicidal function of alveolar macrophages.
- To elucidate the molecular mechanisms underlying impaired bacterial clearance in COPD.
Main Methods:
- Alveolar macrophages were isolated from healthy donors and COPD patients.
- Macrophage apoptosis, bactericidal activity, and mitochondrial reactive oxygen species (mROS) production were assessed.
- A transgenic mouse model (CD68.hMcl-1) was utilized to study Mcl-1's role in COPD.
Main Results:
- COPD AMs exhibited elevated Mcl-1 levels and reduced delayed intracellular bacterial killing.
- Transgenic mice with Mcl-1 overexpression showed impaired bacterial clearance and increased neutrophilic inflammation.
- Mcl-1 dysregulation in COPD macrophages impaired mROS production, crucial for bacterial killing.
Conclusions:
- Upregulation of Mcl-1 and chronic oxidative stress adaptions alter mitochondrial metabolism and macrophage microbicidal function in COPD.
- This leads to a reduced capacity for intracellular bacterial clearance in the delayed phase.
- Targeting Mcl-1 and mitochondrial pathways may offer therapeutic strategies for COPD.
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