title: Nitric oxide levels regulate macrophage commitment to apoptosis or necrosis during pneumococcal infection.
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.
authors.affiliation: Division of Genomic Medicine, University of Sheffield School of Medicine and Biomedical Sciences, Sheffield, UK.
authors.forename: Helen M
authors.initials: HM
authors.lastname: Marriott
authors.forename: Farzana
authors.initials: F
authors.lastname: Ali
authors.forename: Robert C
authors.initials: RC
authors.lastname: Read
authors.forename: Tim J
authors.initials: TJ
authors.lastname: Mitchell
authors.forename: Moira K B
authors.initials: MK
authors.lastname: Whyte
authors.forename: David H
authors.initials: DH
authors.lastname: Dockrell
mesh_terms: D000328:Adult; D017209:Apoptosis; D001426:Bacterial Proteins / Q000494:pharmacology; D001865:Bongkrekic Acid / Q000494:pharmacology; D020169:Caspases / Q000502:physiology; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology / Q000382:microbiology / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D009336:Necrosis; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D010539:Permeability; D010587:Phagocytosis; D011008:Pneumococcal Infections / Q000276:immunology*; D013296:Streptococcus pneumoniae / Q000502:physiology*; D013301:Streptolysins / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D013301:Streptolysins; C032290:plY protein, Streptococcus pneumoniae; D001865:Bongkrekic Acid; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D020169:Caspases