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Alveolar macrophage apoptosis-associated bacterial killing helps prevent murine pneumonia

Alveolar macrophage apoptosis-associated bacterial killing helps prevent murine pneumonia
Alveolar macrophage apoptosis-associated bacterial killing helps prevent murine pneumonia

Rationalle: 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.

Journal Article
1073-449X
84-97
Preston, Julie A.
8e85b8aa-77ce-495e-8b7f-b51864102c6e
Bewley, Martin A.
1412f184-67e0-4fe7-8692-db253d411471
Marriott, Helen M.
34ca8904-d637-4081-b34c-12be45ecef9f
Houghton, A. McGarry
8a098f58-68bd-4090-b644-a316ca20d485
Mohasin, Mohamed
a0667d9b-e09a-4568-b223-80d5a3840ebd
Jubrail, Jamil
a90012af-fe69-40cd-8adb-a342a194d7b4
Morris, Lucy
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Stephenson, Yvonne L.
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Cross, Simon
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Greaves, David R.
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Craig, Ruth W.
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van Rooijen, Nico
bce474c9-0902-4f47-b335-2b98745abe7a
Bingle, Colin D.
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Read, Robert C.
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Mitchell, Timothy J.
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Whyte, Moira K. B.
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Shapiro, Steven D.
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Dockrell, David H.
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Preston, Julie A.
8e85b8aa-77ce-495e-8b7f-b51864102c6e
Bewley, Martin A.
1412f184-67e0-4fe7-8692-db253d411471
Marriott, Helen M.
34ca8904-d637-4081-b34c-12be45ecef9f
Houghton, A. McGarry
8a098f58-68bd-4090-b644-a316ca20d485
Mohasin, Mohamed
a0667d9b-e09a-4568-b223-80d5a3840ebd
Jubrail, Jamil
a90012af-fe69-40cd-8adb-a342a194d7b4
Morris, Lucy
0c0614a6-40c7-4767-97ee-fd9f438586ff
Stephenson, Yvonne L.
5ecfbe80-b5d5-4a4d-acba-e3c1ae508096
Cross, Simon
68e0cf0b-51a0-4f41-9b68-240e8c6be43b
Greaves, David R.
500bd044-f949-469d-afbb-b4a8e799547e
Craig, Ruth W.
3449fcc5-3f49-406d-8b65-650b53b11784
van Rooijen, Nico
bce474c9-0902-4f47-b335-2b98745abe7a
Bingle, Colin D.
9a639961-c20a-4da0-9ce1-ddb2b9e81a69
Read, Robert C.
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Mitchell, Timothy J.
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Whyte, Moira K. B.
fed8c25b-ced7-4a16-89f3-b93208a63a18
Shapiro, Steven D.
73602495-5cbb-46d7-bd0b-ddd7983ea3f0
Dockrell, David H.
a068c9bf-35b8-4c10-8f91-58639cfeca0b

Preston, Julie A., Bewley, Martin A., Marriott, Helen M., Houghton, A. McGarry, Mohasin, Mohamed, Jubrail, Jamil, Morris, Lucy, Stephenson, Yvonne L., Cross, Simon, Greaves, David R., Craig, Ruth W., van Rooijen, Nico, Bingle, Colin D., Read, Robert C., Mitchell, Timothy J., Whyte, Moira K. B., Shapiro, Steven D. and Dockrell, David H. (2019) Alveolar macrophage apoptosis-associated bacterial killing helps prevent murine pneumonia. American Journal of Respiratory and Critical Care Medicine, 200 (1), 84-97. (doi:10.1164/rccm.201804-0646OC).

Record type: Article

Abstract

Rationalle: 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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More information

Accepted/In Press date: 14 January 2019
e-pub ahead of print date: 16 January 2019
Published date: 1 July 2019
Keywords: Journal Article

Identifiers

Local EPrints ID: 430230
URI: http://eprints.soton.ac.uk/id/eprint/430230
ISSN: 1073-449X
PURE UUID: c31b54a4-9d52-4f5f-b471-8ff366727bac
ORCID for Robert C. Read: ORCID iD orcid.org/0000-0002-4297-6728

Catalogue record

Date deposited: 16 Apr 2019 16:30
Last modified: 26 Nov 2021 02:58

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Contributors

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

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