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Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance

Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance
Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance

Macrophages are critical effectors of bacterial clearance and must retain viability, despite exposure to toxic bacterial products, until key antimicrobial functions are performed. Subsequently, host-mediated macrophage apoptosis aids resolution of infection. The ability of macrophages to make this transition from resistance to susceptibility to apoptosis is important for effective host innate immune responses. We investigated the role of Mcl-1, an essential regulator of macrophage lifespan, in this switch from viability to apoptosis, using the model of pneumococcal-associated macrophage apoptosis. Upon exposure to pneumococci, macrophages initially upregulate Mcl-1 protein and maintain viability for up to 14 hours. Subsequently, macrophages reduce expression of full-length Mcl-1 and upregulate a 34-kDa isoform of Mcl-1 corresponding to a novel BH3-only splice variant, Mcl-1(Exon-1). Change in expression of Mcl-1 protein is associated with mitochondrial membrane permeabilization, which is characterized by loss of mitochondrial inner transmembrane potential and translocation of cytochrome c and apoptosis-inducing factor. Following pneumococcal infection, macrophages expressing full-length human Mcl-1 as a transgene exhibit a delay in apoptosis and in bacterial killing. Mcl-1 transgenic mice clear pneumococci from the lung less efficiently than nontransgenic mice. Dynamic changes in Mcl-1 expression determine macrophage viability as well as antibacterial host defense.

Alternative Splicing, Animals, Apoptosis, Cell Survival, Gene Expression Regulation, Humans, Macrophages, Membrane Potentials, Mice, Mice, Transgenic, Mitochondria, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Proteins, Pneumonia, Pneumococcal, Protein Isoforms, Proto-Oncogene Proteins c-bcl-2, Streptococcus pneumoniae, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.
0021-9738
359-68
Marriott, Helen M
34ca8904-d637-4081-b34c-12be45ecef9f
Bingle, Colin D
9a639961-c20a-4da0-9ce1-ddb2b9e81a69
Read, Robert C
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Braley, Karen E
8155f5cd-f50f-40b3-9fcb-58325539996b
Kroemer, Guido
b8513b5d-ef12-460c-b8c5-7c8eb08f9f26
Hellewell, Paul G
312c2550-001d-4330-97ba-a6add658ffa0
Craig, Ruth W
3449fcc5-3f49-406d-8b65-650b53b11784
Whyte, Moira K B
fed8c25b-ced7-4a16-89f3-b93208a63a18
Dockrell, David H
a068c9bf-35b8-4c10-8f91-58639cfeca0b
Marriott, Helen M
34ca8904-d637-4081-b34c-12be45ecef9f
Bingle, Colin D
9a639961-c20a-4da0-9ce1-ddb2b9e81a69
Read, Robert C
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Braley, Karen E
8155f5cd-f50f-40b3-9fcb-58325539996b
Kroemer, Guido
b8513b5d-ef12-460c-b8c5-7c8eb08f9f26
Hellewell, Paul G
312c2550-001d-4330-97ba-a6add658ffa0
Craig, Ruth W
3449fcc5-3f49-406d-8b65-650b53b11784
Whyte, Moira K B
fed8c25b-ced7-4a16-89f3-b93208a63a18
Dockrell, David H
a068c9bf-35b8-4c10-8f91-58639cfeca0b

Marriott, Helen M, Bingle, Colin D, Read, Robert C, Braley, Karen E, Kroemer, Guido, Hellewell, Paul G, Craig, Ruth W, Whyte, Moira K B and Dockrell, David H (2005) Dynamic changes in Mcl-1 expression regulate macrophage viability or commitment to apoptosis during bacterial clearance. Journal of Clinical Investigation, 115 (2), 359-68. (doi:10.1172/JCI21766).

Record type: Article

Abstract

Macrophages are critical effectors of bacterial clearance and must retain viability, despite exposure to toxic bacterial products, until key antimicrobial functions are performed. Subsequently, host-mediated macrophage apoptosis aids resolution of infection. The ability of macrophages to make this transition from resistance to susceptibility to apoptosis is important for effective host innate immune responses. We investigated the role of Mcl-1, an essential regulator of macrophage lifespan, in this switch from viability to apoptosis, using the model of pneumococcal-associated macrophage apoptosis. Upon exposure to pneumococci, macrophages initially upregulate Mcl-1 protein and maintain viability for up to 14 hours. Subsequently, macrophages reduce expression of full-length Mcl-1 and upregulate a 34-kDa isoform of Mcl-1 corresponding to a novel BH3-only splice variant, Mcl-1(Exon-1). Change in expression of Mcl-1 protein is associated with mitochondrial membrane permeabilization, which is characterized by loss of mitochondrial inner transmembrane potential and translocation of cytochrome c and apoptosis-inducing factor. Following pneumococcal infection, macrophages expressing full-length human Mcl-1 as a transgene exhibit a delay in apoptosis and in bacterial killing. Mcl-1 transgenic mice clear pneumococci from the lung less efficiently than nontransgenic mice. Dynamic changes in Mcl-1 expression determine macrophage viability as well as antibacterial host defense.

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More information

Published date: February 2005
Keywords: Alternative Splicing, Animals, Apoptosis, Cell Survival, Gene Expression Regulation, Humans, Macrophages, Membrane Potentials, Mice, Mice, Transgenic, Mitochondria, Myeloid Cell Leukemia Sequence 1 Protein, Neoplasm Proteins, Pneumonia, Pneumococcal, Protein Isoforms, Proto-Oncogene Proteins c-bcl-2, Streptococcus pneumoniae, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.

Identifiers

Local EPrints ID: 416428
URI: http://eprints.soton.ac.uk/id/eprint/416428
ISSN: 0021-9738
PURE UUID: 700248c9-b3ec-41bb-9c8d-0fda7b1597dd
ORCID for Robert C Read: ORCID iD orcid.org/0000-0002-4297-6728

Catalogue record

Date deposited: 15 Dec 2017 17:30
Last modified: 10 Nov 2021 03:30

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Contributors

Author: Helen M Marriott
Author: Colin D Bingle
Author: Robert C Read ORCID iD
Author: Karen E Braley
Author: Guido Kroemer
Author: Paul G Hellewell
Author: Ruth W Craig
Author: Moira K B Whyte
Author: David H Dockrell

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