Preston, J.A., Bewley, M.A., Marriott, H.M. orcid.org/0000-0003-1070-0054 et al. (15 more authors) (2019) Alveolar macrophage apoptosis-associated bacterial killing helps prevent murine pneumonia. American Journal of Respiratory and Critical Care Medicine, 200 (1). pp. 84-97. ISSN 1073-449X
Abstract
RATIONALE: Antimicrobial resistance challenges therapy of pneumonia. Enhancing macrophage microbicidal responses would combat this problem but is limited by our understanding of how alveolar macrophages (AM) kill bacteria. OBJECTIVES: To define the role and mechanism of AM apoptosis-associated bacterial killing in the lung. METHODS: We generated a unique CD68.hMcl-1 transgenic mouse with macrophage-specific over-expression of the human anti-apoptotic Mcl-1 protein, a factor upregulated in AM from patients at increased risk of community-acquired pneumonia, to address the requirement for apoptosis-associated killing. MEASUREMENTS AND MAIN RESULTS: Wild-type and transgenic macrophages demonstrated comparable ingestion and initial phagolysosomal killing of bacteria. Continued ingestion (for > 12 h) overwhelmed initial killing and a second late-phase microbicidal response killed viable bacteria in wild-type macrophages, but this response was blunted in CD68.hMcl-1 transgenic macrophages. The late-phase of bacterial killing required both caspase-induced generation of mitochondrial reactive oxygen species (mROS) and nitric oxide (NO), whose peak generation coincided with the late-phase of killing. The CD68.hMcl-1 transgene prevented mROS but not NO generation. Apoptosis-associated killing enhanced pulmonary clearance of Streptococcus pneumoniae and Haemophilus influenzae in wild-type but not CD68.hMcl-1 transgenic mice. Bacterial clearance was enhanced in vivo in CD68.hMcl-1 transgenic mice by reconstitution of apoptosis with BH3 mimetics or clodronate-encapsulated liposomes. Apoptosis-associated killing was not activated during Staphylococcus aureus lung infection. CONCLUSIONS: Mcl-1 upregulation prevents macrophage apoptosis-associated killing and establishes that apoptosis-associated killing is required to allow AM to clear ingested bacteria. Engagement of macrophage apoptosis should be investigated as a novel host-based antimicrobial strategy.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2019 American Thoracic Society. This is an author produced version of a paper subsequently published in American Journal of Respiratory and Critical Care Medicine. Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | Apoptosis; Bacteria; Macrophage; Mcl-1; Pneumonia |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Sheffield Teaching Hospitals |
Funding Information: | Funder Grant number MEDICAL RESEARCH COUNCIL MR/M017931/1 MEDICAL RESEARCH COUNCIL MR/N02995X/1 |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 23 Jan 2019 11:47 |
Last Modified: | 16 Nov 2021 12:18 |
Status: | Published |
Publisher: | American Thoracic Society |
Refereed: | Yes |
Identification Number: | 10.1164/rccm.201804-0646OC |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:141496 |