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Distinct Cell Death Programs in Monocytes Regulate Innate Responses Following Challenge with Common Causes of Invasive Bacterial Disease

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Original languageEnglish
Pages (from-to)2968-2979
Number of pages12
JournalJournal of Immunology
Volume185
Issue number5
DOIs
Publication statusPublished - 1 Sep 2010

Abstract

Peripheral blood monocytes represent the rapid response component of mononuclear phagocyte host defense, generating vigorous but finite antibacterial responses. We investigated the fate of highly purified primary human monocytes following phagocytosis of different bacteria. Exposure to high bacterial loads resulted in rapid loss of cell viability and decreased functional competence. Cell death typically involved classical apoptosis. Exposure to high numbers of Escherichia coli and Klebsiella pneumoniae induced nonapoptotic death with loss of cell membrane integrity, marked disruption of phagolysosomes, and caspase-1 activation, while a subset of cells also released caspase-1-regulated extracellular traps. Classical apoptosis increased if extracellular bacterial replication was reduced and decreased if intracellular ATP levels were reduced during these infections. Both classical apoptosis and the alternative forms of cell death allowed monocytes, whose functional competence was exhausted, to down-regulate reactive oxygen species and proinflammatory cytokine responses. In contrast, sustained stimulation of glycolytic metabolism and mitochondrial oxidative phosphorylation, with associated hypoxia inducible factor-1 alpha upregulation, maintained intracellular ATP levels and prolonged monocyte functional longevity, as assessed by maintenance of phagocytosis, reactive oxygen species production, and proinflammatory cytokine generation. Monocyte innate responses to bacteria are short-lived and are limited by an intrinsic program of apoptosis, a response that is subverted by overwhelming infection with E. coli and K. pneumoniae or bacterial stimulation of cell metabolism. In this regard, the fate of monocytes following bacterial challenge more closely resembles neutrophils than macrophages. The Journal of Immunology, 2010, 185: 2968-2979.

    Research areas

  • NEUTROPHIL EXTRACELLULAR TRAPS, UPPER RESPIRATORY-TRACT, STREPTOCOCCUS-PNEUMONIAE, MACROPHAGE DIFFERENTIATION, MONONUCLEAR PHAGOCYTES, NEISSERIA-MENINGITIDIS, MENINGOCOCCAL DISEASE, ALVEOLAR MACROPHAGE, LYSOSOMAL PATHWAY, IN-VITRO

ID: 17165540