CD14-dependent clearance of apoptotic cells by human macrophages: the role of phosphatidylserine

Devitt, Andrew; Pierce, Sarah; Oldreive, Ceri; Shingler, William; Gregory, Christopher D.

doi:10.1038/sj.cdd.4401168

Cited by 78 publications

(61 citation statements)

References 51 publications

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“…42 In either case, the present studies suggest strongly that the plasma-membrane changes that are sufficient for phagocytic clearance of apoptotic cells occur independently of caspase-3 activation. Since it is now becoming clear that, in addition to PS exposure, further changes at the surface of dying cells are required for phagocytic clearance by macrophages, 43 the present results indicate that caspase-3 is dispensable for the Figure 8 Suppression of TNF-a production by macrophages exposed to etoposide-treated MCF-7 cells. Human monocyte-derived macrophages (7 days) were either cultured alone (stippled bars) or were exposed to etoposide-treated, detached MCF-7-N1 (striped bars) or MCF-7-C3 cells (black bars) in the presence (right half of figure) or absence (left half) of LPS.…”

Section: Discussionmentioning

confidence: 68%

Macrophage-mediated clearance of cells undergoing caspase-3-independent death

et al. 2003

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Little is known of the functions of caspases in mediating the surface changes required for phagocytosis of dying cells. Here we investigate the role played by the effector caspase, caspase-3 in this process using the caspase-3-defective MCF-7 breast carcinoma line and derived caspase-3-expressing transfectants. Our results indicate that, while certain typical features of apoptosis induced by etoposide -namely classical morphological changes and the ability to degrade DNA into oligonucleosomal fragments -are caspase-3-dependent, loss of cell adhesion to plastic and the capacity to interact with, and to be phagocytosed by, human monocyte-derived macrophages -both by CD14-dependent and CD14-independent mechanisms -do not require caspase-3. Furthermore, both etoposide-induced caspase-3-positive and -negative MCF-7 cells suppressed proinflammatory cytokine release by macrophages. These results demonstrate directly that cell surface changes that are sufficient for anti-inflammatory clearance by human macrophages can be regulated independently of stereotypical features of the apoptosis programme that require caspase-3.

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Section: Discussionmentioning

confidence: 68%

Macrophage-mediated clearance of cells undergoing caspase-3-independent death

et al. 2003

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“…However, CD14 appears unlikely to bind preferentially to apoptotic-cell-associated PS, and does not function as a PS-receptor on HMDMs. 32 It remains unclear as to whether CD36 mediates the engulfment of apoptotic cells via direct binding to PS. 11 The results of the present study suggest that stabilin-2 is a strong candidate for a PS-specific membrane receptor.…”

Section: Discussionmentioning

confidence: 99%

Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor

et al. 2007

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Rapid phagocytic clearance of apoptotic cells is crucial for the prevention of both inflammation and autoimmune responses. Phosphatidylserine (PS) at the external surface of the plasma membrane has been proposed to function as a general 'eat me' signal for apoptotic cells. Although several soluble bridging molecules have been suggested for the recognition of PS, the PS-specific membrane receptor that binds directly to the exposed PS and provides a tickling signal has yet to be definitively identified. In this study, we provide evidence that stabilin-2 is a novel PS receptor, which performs a key function in the rapid clearance of cell corpses. It recognizes PS on aged red blood cells and apoptotic cells, and mediates their engulfment. The downregulation of stabilin-2 expression in macrophages significantly inhibits phagocytosis, and anti-stabilin-2 monoclonal antibody provokes the release of the anti-inflammatory cytokine, transforming growth factor-b. Furthermore, the results of timelapse video analyses indicate that stabilin-2 performs a crucial function in the rapid clearance of aged and apoptotic cells. These data indicate that stabilin-2 is the first of the membrane PS receptors to provide tethering and tickling signals, and may also be involved in the resolution of inflammation and the prevention of autoimmunity.

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“…PMNs in RPMI 1640 medium plus 0.25% BSA were incubated at 37°C for 24 h to encourage spontaneous apoptosis, washed in HBSS, and resuspended in RPMI 1640 medium (Invitrogen Life Technologies). Apoptosis was assessed routinely by fluorescence microscopy of 4Ј,6Ј-diamidino-2-phenylindole (DAPI; Sigma-Aldrich) (25) or by morphological assessment of H&E-stained cells following cytocentrifugation.…”

Section: Induction and Measurement Of Apoptosismentioning

confidence: 99%

Enhanced Apoptotic Cell Clearance Capacity and B Cell Survival Factor Production by IL-10-Activated Macrophages: Implications for Burkitt’s Lymphoma

Ogden

Pound

Batth

et al. 2005

The Journal of Immunology

127

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Burkitt’s lymphoma (BL) is typified by frequent tumor cell apoptosis and significant macrophage infiltration. Since BL cells have an inherent tendency to undergo apoptosis at a high rate, we reasoned that macrophages in BL are functionally enhanced in at least two activities that have implications for tumor pathogenesis: 1) engulfment of apoptotic cells, an anti-inflammatory process known to suppress immune responses, and 2) production of BL cell survival factors that limit the extent of tumor cell apoptosis. In this study, we show that the microenvironment of BL is rich in the pleiotropic cytokine IL-10, which can be produced by both tumor cells and macrophages, and that IL-10-activated human macrophages have enhanced capacity to engulf apoptotic cells in vitro. This was found to be dependent on the macrophage tethering receptor of apoptotic cells, CD14. Furthermore, IL-10-activated macrophages were found to produce markedly higher levels of the B cell survival factor, B cell-activating factor of the TNF family/B lymphocyte stimulator (BAFF/BLyS) than macrophages matured in the absence of IL-10. Coculture of macrophages with BL cells further enhanced BAFF secretion. Significantly, we show that enhancement of BL cell survival by IL-10-activated macrophages is mediated by a BAFF-dependent component and that BAFF is produced at high levels by tumor-associated macrophages in situ. These results indicate that macrophages, regulated by IL-10, have the potential to promote BL pathogenesis, first, through suppression of antitumor immunity following enhanced engulfment of apoptotic tumor cells and, second, through increased production of tumor cell growth/survival factors.

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CD14-dependent clearance of apoptotic cells by human macrophages: the role of phosphatidylserine

Cited by 78 publications

References 51 publications

Macrophage-mediated clearance of cells undergoing caspase-3-independent death

Macrophage-mediated clearance of cells undergoing caspase-3-independent death

Rapid cell corpse clearance by stabilin-2, a membrane phosphatidylserine receptor

Enhanced Apoptotic Cell Clearance Capacity and B Cell Survival Factor Production by IL-10-Activated Macrophages: Implications for Burkitt’s Lymphoma

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