Alveolar macrophage apoptosis-associated bacterial killing helps prevent murine pneumonia
Research output: Contribution to journal › Article › peer-review
Colleges, School and Institutes
- University of Sheffield
- University of Washington, Fred Hutchison Medical Center, Division of Pulmonary, Critical Care and Sleep Medicine, Seattle, Washington, United States.
- University of Dhaka, Department of Biochemistry and Molecular Biology, Dhaka, Bangladesh.
- Sheffield Teaching Hospitals, Sheffield, United Kingdom of Great Britain and Northern Ireland.
- University of Oxford, Sir William Dunn School of Pathology, Oxford, United Kingdom of Great Britain and Northern Ireland ; firstname.lastname@example.org.
- Geisel School of Medicine at Dartmouth, Department of Pharmacology and Toxicology, Dartmouth, New Hampshire, United States.
- VU University Medical Center, Department of Molecular Cell Biology and Immunology, Amsterdam, Netherlands.
- University of Southampton Medical School and NIHR Southampton Biomedical Research Centre, Southampton, United Kingdom of Great Britain and Northern Ireland.
- The University of Edinburgh , Department of Respiratory Medicine and MRC Centre for Inflammation Research, Edinburgh, United Kingdom of Great Britain and Northern Ireland.
- University of Pittsburgh Medical Center, Division of Pulmonary, Allergy and Critical Care Medicine, Pittsburgh, Pennsylvania, United States.
- University of Edinburgh, Department of Infection Medicine and MRC Centre for Inflammation Reserach, Edinburgh, United Kingdom of Great Britain and Northern Ireland ; David.Dockrell@ed.ac.uk.
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 (AMs) 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 overexpression of the human antiapoptotic Mcl-1 protein, a factor upregulated in AMs 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 and nitric oxide, the peak generation of which coincided with the late phase of killing. The CD68.hMcl-1 transgene prevented mitochondrial reactive oxygen species but not nitric oxide generation. Apoptosis-associated killing enhanced pulmonary clearance of Streptococcus pneumoniae and Haemophilus influenzae in wild-type mice 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 AMs to clear ingested bacteria. Engagement of macrophage apoptosis should be investigated as a novel, host-based antimicrobial strategy.
|Number of pages||14|
|Journal||American Journal of Respiratory and Critical Care Medicine|
|Early online date||16 Jan 2019|
|Publication status||Published - 1 Jul 2019|
- Apoptosis, Bacteria, Macrophage, Mcl-1, Pneumonia