Alveolar macrophage apoptosis-associated bacterial killing helps prevent murine pneumonia
<p><strong>RATIONALE:</strong> 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.</p> <p><strong>OBJECT...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
American Thoracic Society
2019
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| _version_ | 1797080727173464064 |
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| author | Preston, J Bewley, M Marriott, H Houghton, A Mohasin, M Jubrail, J Morris, L Stephenson, Y Cross, S Greaves, D Craig, R Van Rooijen, N Bingle, C Read, R Mitchell, T Whyte, M Shapiro, S Dockrell, D |
| author_facet | Preston, J Bewley, M Marriott, H Houghton, A Mohasin, M Jubrail, J Morris, L Stephenson, Y Cross, S Greaves, D Craig, R Van Rooijen, N Bingle, C Read, R Mitchell, T Whyte, M Shapiro, S Dockrell, D |
| author_sort | Preston, J |
| collection | OXFORD |
| description | <p><strong>RATIONALE:</strong> 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.</p> <p><strong>OBJECTIVES:</strong> To define the role and mechanism of AM apoptosis-associated bacterial killing in the lung.</p> <p><strong>METHODS:</strong> 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.</p> <p><strong>MEASUREMENTS AND MAIN RESULTS:</strong> 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.</p> <p><strong>CONCLUSIONS:</strong> 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.</p> |
| first_indexed | 2024-03-07T01:04:16Z |
| format | Journal article |
| id | oxford-uuid:8ac9794a-3595-4c0c-b77a-a383c4ad1ddb |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:04:16Z |
| publishDate | 2019 |
| publisher | American Thoracic Society |
| record_format | dspace |
| spelling | oxford-uuid:8ac9794a-3595-4c0c-b77a-a383c4ad1ddb2022-03-26T22:33:57ZAlveolar macrophage apoptosis-associated bacterial killing helps prevent murine pneumoniaJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:8ac9794a-3595-4c0c-b77a-a383c4ad1ddbEnglishSymplectic Elements at OxfordAmerican Thoracic Society2019Preston, JBewley, MMarriott, HHoughton, AMohasin, MJubrail, JMorris, LStephenson, YCross, SGreaves, DCraig, RVan Rooijen, NBingle, CRead, RMitchell, TWhyte, MShapiro, SDockrell, D<p><strong>RATIONALE:</strong> 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.</p> <p><strong>OBJECTIVES:</strong> To define the role and mechanism of AM apoptosis-associated bacterial killing in the lung.</p> <p><strong>METHODS:</strong> 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.</p> <p><strong>MEASUREMENTS AND MAIN RESULTS:</strong> 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.</p> <p><strong>CONCLUSIONS:</strong> 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.</p> |
| spellingShingle | Preston, J Bewley, M Marriott, H Houghton, A Mohasin, M Jubrail, J Morris, L Stephenson, Y Cross, S Greaves, D Craig, R Van Rooijen, N Bingle, C Read, R Mitchell, T Whyte, M Shapiro, S Dockrell, D Alveolar macrophage apoptosis-associated bacterial killing helps prevent murine pneumonia |
| title | Alveolar macrophage apoptosis-associated bacterial killing helps prevent murine pneumonia |
| title_full | Alveolar macrophage apoptosis-associated bacterial killing helps prevent murine pneumonia |
| title_fullStr | Alveolar macrophage apoptosis-associated bacterial killing helps prevent murine pneumonia |
| title_full_unstemmed | Alveolar macrophage apoptosis-associated bacterial killing helps prevent murine pneumonia |
| title_short | Alveolar macrophage apoptosis-associated bacterial killing helps prevent murine pneumonia |
| title_sort | alveolar macrophage apoptosis associated bacterial killing helps prevent murine pneumonia |
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