Elucidation of molecular events leading to neutrophil apoptosis following phagocytosis. Cross-talk between caspase 8, reactive oxygen species, and MAPK/ERK activation

Bin Zhang, Junichi Hirahashi, Xavier Cullere, Tanya N. Mayadas

Research output: Contribution to journalArticle

177 Citations (Scopus)

Abstract

Phagocytosis of complement-opsonized targets is a primary function of neutrophils at sites of inflammation, and the clearance of neutrophils that have phagocytosed microbes is important for the resolution of inflammation. Our previous work suggests that phagocytosis leads to rapid neutrophil apoptosis that is inhibited by antibody to the β2 integrin, Mac-1, and requires NADPH oxidase-derived reactive oxygen species (ROS) generated during phagocytosis. Here we report that phagocytosis-induced cell death (PICD) does not occur in Mac-1-deficient murine neutrophils, suggesting that PICD proceeds through a bona fide Mac-1-dependent pathway. A sustained, intracellular oxidative burst is associated with PICD. Furthermore, PICD does not require traditional death receptors, Fas, or tumor necrosis factor (TNF) receptor. TNF but not Fas synergizes with phagocytosis to enhance significantly PICD by increasing the oxidative burst, and this is Mac-1-dependent. Phagocytosis-induced ROS promote cleavage/activation of caspases 8 and 3, key players in most extrinsic ("death receptor") mediated pathways of apoptosis, and caspases 8 and 3 but not caspase 9/mitochondria, are required for PICD. This suggests that ROS target the extrinsic versus the intrinsic ("stress stimulus") apoptotic pathway. Phagocytosis also triggers a competing MAPK/ERK-dependent survival pathway that provides resistance to PICD likely by down-regulating caspase 8 activation. The anti-apoptotic factor granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly enhances ROS generation associated with phagocytosis. Despite this, it completely suppresses PICD by sustaining ERK activation and inhibiting caspase 8 activation in phagocytosing neutrophils. Together, these studies suggest that Mac-1-mediated phagocytosis promotes apoptosis through a caspase 8/3-dependent pathway that is modulated by NADPH oxidase-generated ROS and MAPK/ERK. Moreover, TNF and GM-CSF, likely encountered by phagocytosing neutrophils at inflammatory sites, exploit pro-(ROS) and anti-apoptotic (ERK) signals triggered by phagocytosis to promote or suppress PICD, respectively, and thus modulate the fate of phagocytosing neutrophils.

Original languageEnglish
Pages (from-to)28443-28454
Number of pages12
JournalJournal of Biological Chemistry
Volume278
Issue number31
DOIs
Publication statusPublished - 2003 Aug 1
Externally publishedYes

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Caspase 8
Cell death
Phagocytosis
Reactive Oxygen Species
Neutrophils
Chemical activation
Apoptosis
Cell Death
Death Domain Receptors
NADPH Oxidase
Granulocyte-Macrophage Colony-Stimulating Factor
Caspase 3
Tumor Necrosis Factor-alpha
Mitochondria
Caspase 9
Tumor Necrosis Factor Receptors
Integrins
Respiratory Burst
Antibodies
Inflammation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Elucidation of molecular events leading to neutrophil apoptosis following phagocytosis. Cross-talk between caspase 8, reactive oxygen species, and MAPK/ERK activation. / Zhang, Bin; Hirahashi, Junichi; Cullere, Xavier; Mayadas, Tanya N.

In: Journal of Biological Chemistry, Vol. 278, No. 31, 01.08.2003, p. 28443-28454.

Research output: Contribution to journalArticle

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