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Am J Respir Crit Care Med. 2019 Jul 1;200(1):84-97. doi: 10.1164/rccm.201804-0646OC.

Alveolar Macrophage Apoptosis-associated Bacterial Killing Helps Prevent Murine Pneumonia.

Author information

1
1 The Florey Institute for Host-Pathogen Interactions and.
2
2 Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, United Kingdom.
3
3 Clinical Research Division, Fred Hutchinson Cancer Research Center, and.
4
4 Division of Pulmonary and Critical Care Medicine, University of Washington, Seattle, Washington.
5
5 Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh.
6
6 MRC Centre for Inflammation Research.
7
7 Sheffield Teaching Hospitals, Sheffield, United Kingdom.
8
8 Sir William Dunn School of Pathology, University of Oxford, Oxford, United Kingdom.
9
9 Department of Pharmacology and Toxicology, Geissel School of Medicine at Dartmouth, Hanover, New Hampshire.
10
10 Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, the Netherlands.
11
11 University of Southampton Medical School, Southampton, United Kingdom.
12
12 National Institute for Health Research Southampton Biomedical Research Centre, Southampton, United Kingdom.
13
13 Institute of Microbiology and Infection, School of Immunity and Infection, University of Birmingham, Birmingham, United Kingdom; and.
14
14 Department of Respiratory Medicine, and.
15
15 Division of Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
16
16 Infection Medicine, University of Edinburgh, Edinburgh, United Kingdom.

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 (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.

KEYWORDS:

Mcl-1; apoptosis; bacteria; macrophage; pneumonia

PMID:
30649895
PMCID:
PMC6603058
[Available on 2020-01-01]
DOI:
10.1164/rccm.201804-0646OC
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