Alveolar macrophage apoptosis-associated bacterial killing helps prevent murine pneumonia

Research output: Contribution to journalArticle

Authors

  • Julie A Preston
  • Martin A Bewley
  • Helen M Marriott
  • A McGarry Houghton
  • Mohamed Mohasin
  • Jamil Jubrail
  • Lucy Morris
  • Yvonne L Stephenson
  • Simon Cross
  • David R Greaves
  • Ruth W Craig
  • Nico van Rooijen
  • Colin D Bingle
  • Robert C Read
  • Moira K B Whyte
  • Steven D Shapiro
  • David H Dockrell

Colleges, School and Institutes

External organisations

  • 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 ; carlota.recio@path.ox.ac.uk.
  • 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.

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.

Details

Original languageEnglish
Pages (from-to)84-97
Number of pages14
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume200
Issue number1
Early online date16 Jan 2019
Publication statusPublished - 1 Jul 2019

Keywords

  • Apoptosis, Bacteria, Macrophage, Mcl-1, Pneumonia