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Alveolar Macrophage Apoptosis-associated Bacterial Killing Helps Prevent Murine Pneumonia.
Preston, Julie A. 1,2,*; Bewley, Martin A. 1,2,*; Marriott, Helen M. 1,2,*; McGarry Houghton, A. 3,4; Mohasin, Mohammed 5; Jubrail, Jamil 6; Morris, Lucy 1,2; Stephenson, Yvonne L. 1,2; Cross, Simon 1,2,7; Greaves, David R. 8; Craig, Ruth W. 9; van Rooijen, Nico 10; Bingle, Colin D. 1,2; Read, Robert C. 11,12; Mitchell, Timothy J. 13; Whyte, Moira K. B. 6,14; Shapiro, Steven D. 15; Dockrell, David H. 6,16
[Article] American Journal of Respiratory & Critical Care Medicine. 200(1):84-97, July 1, 2019.

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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.