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J. Biol. Chem., Vol. 278, Issue 31, 28443-28454, August 1, 2003
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Elucidation of Molecular Events Leading to Neutrophil Apoptosis following Phagocytosis
CROSS-TALK BETWEEN CASPASE 8, REACTIVE OXYGEN SPECIES, AND MAPK/ERK ACTIVATION*
From the Vascular Research Division, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115
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 
2 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.
Received for publication, October 20, 2002 , and in revised form, May 5, 2003.
* This work was supported by National Institutes of Health Grant PO1-HL36028. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Both authors contributed equally to this work.
To whom correspondence should be addressed. Tel.: 617-278-0194; Fax:
617-732-5933; E-mail:
tmayadas{at}rics.bwh.harvard.edu.
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