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Nitric oxide levels regulate macrophage commitment to apoptosis or necrosis during pneumococcal infection

Nitric oxide levels regulate macrophage commitment to apoptosis or necrosis during pneumococcal infection
Nitric oxide levels regulate macrophage commitment to apoptosis or necrosis during pneumococcal infection

Macrophages are resistant to constitutive apoptosis, but infectious stimuli can induce either microbial or host-mediated macrophage apoptosis. Phagocytosis and killing of opsonized pneumococci by macrophages are potent stimuli for host-mediated apoptosis, but the link between pneumococcal killing and apoptosis induction remains undefined. We now show phagocytosis of pneumococci by differentiated human monocyte-derived macrophages (MDM) results in up-regulation of inducible nitric oxide synthase (iNOS) and increased production of NO and reactive nitrogen species. NO accumulation in macrophages initiates an apoptotic program that involves NO-dependent mitochondrial membrane permeabilization, Mcl-1 down-regulation, and caspase activation and results in nuclear condensation and fragmentation. An inhibitor of mitochondrial permeability transition, bongkrekic acid, decreases pneumococcal-associated macrophage apoptosis. Conversely, inhibition of NO production using iNOS inhibitors decreases bacterial killing and shifts the cell death program from apoptosis to necrosis. Pneumolysin contributes to both NO production and apoptosis induction. After initial microbial killing, NO accumulation switches the macrophage phenotype from an activated cell to a cell susceptible to apoptosis. These results illustrate important roles for NO in the integration of host defense and regulation of inflammation in human macrophages.

Adult, Apoptosis, Bacterial Proteins, Bongkrekic Acid, Caspases, Cells, Cultured, Enzyme Induction, Enzyme Inhibitors, Humans, Intracellular Membranes, Macrophages, Mitochondria, Necrosis, Nitric Oxide, Nitric Oxide Synthase, Nitric Oxide Synthase Type II, Permeability, Phagocytosis, Pneumococcal Infections, Streptococcus pneumoniae, Streptolysins, omega-N-Methylarginine, Journal Article, Research Support, Non-U.S. Gov't
0892-6638
1126-1128
Marriott, Helen M
34ca8904-d637-4081-b34c-12be45ecef9f
Ali, Farzana
2bf00407-ff59-41e7-8fcf-547cd1dc4f6a
Read, Robert C
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Mitchell, Tim J
d11e17e1-428b-4b7c-a0f3-4e954ea0562c
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
Ali, Farzana
2bf00407-ff59-41e7-8fcf-547cd1dc4f6a
Read, Robert C
b5caca7b-0063-438a-b703-7ecbb6fc2b51
Mitchell, Tim J
d11e17e1-428b-4b7c-a0f3-4e954ea0562c
Whyte, Moira K B
fed8c25b-ced7-4a16-89f3-b93208a63a18
Dockrell, David H
a068c9bf-35b8-4c10-8f91-58639cfeca0b

Marriott, Helen M, Ali, Farzana, Read, Robert C, Mitchell, Tim J, Whyte, Moira K B and Dockrell, David H (2004) Nitric oxide levels regulate macrophage commitment to apoptosis or necrosis during pneumococcal infection. The FASEB Journal, 18 (10), 1126-1128. (doi:10.1096/fj.03-1450fje).

Record type: Article

Abstract

Macrophages are resistant to constitutive apoptosis, but infectious stimuli can induce either microbial or host-mediated macrophage apoptosis. Phagocytosis and killing of opsonized pneumococci by macrophages are potent stimuli for host-mediated apoptosis, but the link between pneumococcal killing and apoptosis induction remains undefined. We now show phagocytosis of pneumococci by differentiated human monocyte-derived macrophages (MDM) results in up-regulation of inducible nitric oxide synthase (iNOS) and increased production of NO and reactive nitrogen species. NO accumulation in macrophages initiates an apoptotic program that involves NO-dependent mitochondrial membrane permeabilization, Mcl-1 down-regulation, and caspase activation and results in nuclear condensation and fragmentation. An inhibitor of mitochondrial permeability transition, bongkrekic acid, decreases pneumococcal-associated macrophage apoptosis. Conversely, inhibition of NO production using iNOS inhibitors decreases bacterial killing and shifts the cell death program from apoptosis to necrosis. Pneumolysin contributes to both NO production and apoptosis induction. After initial microbial killing, NO accumulation switches the macrophage phenotype from an activated cell to a cell susceptible to apoptosis. These results illustrate important roles for NO in the integration of host defense and regulation of inflammation in human macrophages.

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More information

e-pub ahead of print date: 7 May 2004
Published date: July 2004
Keywords: Adult, Apoptosis, Bacterial Proteins, Bongkrekic Acid, Caspases, Cells, Cultured, Enzyme Induction, Enzyme Inhibitors, Humans, Intracellular Membranes, Macrophages, Mitochondria, Necrosis, Nitric Oxide, Nitric Oxide Synthase, Nitric Oxide Synthase Type II, Permeability, Phagocytosis, Pneumococcal Infections, Streptococcus pneumoniae, Streptolysins, omega-N-Methylarginine, Journal Article, Research Support, Non-U.S. Gov't

Identifiers

Local EPrints ID: 416424
URI: https://eprints.soton.ac.uk/id/eprint/416424
ISSN: 0892-6638
PURE UUID: 28455aed-a527-4297-93f8-445d5d757b67
ORCID for Robert C Read: ORCID iD orcid.org/0000-0002-4297-6728

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Date deposited: 15 Dec 2017 17:30
Last modified: 20 Jul 2019 00:42

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Contributors

Author: Helen M Marriott
Author: Farzana Ali
Author: Robert C Read ORCID iD
Author: Tim J Mitchell
Author: Moira K B Whyte
Author: David H Dockrell

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