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Alveolar Macrophage Apoptosis-Associated Bacterial Killing Helps Prevent Murine Pneumonia

Research output: Contribution to journalArticle

  • 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
  • Timothy J Mitchell
  • Moira K B Whyte
  • Steven D Shapiro
  • David H Dockrell

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  • AJRCCM AAK REV1 SUB CLEAN

    Rights statement: Author's peer reviewed manuscript as accepted for publication.

    Accepted author manuscript, 204 KB, Word document

Original languageEnglish
JournalAmerican Journal of Respiratory and Critical Care Medicine
Early online date16 Jan 2019
DOIs
Publication statusE-pub ahead of print - 16 Jan 2019

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.

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