Exposure of phosphatidylserine is a general feature in the phagocytosis of apoptotic lymphocytes by macrophages

Krahling, Stephen; Callahan, Melissa K.; Williamson, Patrick; Schlegel, Robert

doi:10.1038/sj.cdd.4400473

Cited by 190 publications

(173 citation statements)

References 18 publications

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“…The redundancy of receptors involved in this process makes it difficult to identify the dominant receptors and/or block the uptake process on the plasma membrane. Although it is thought that all these receptors may, in part, recognize externalized PS on the surface of apoptotic bodies Hoffmann et al, 2001;Krahling et al, 1999), this has not been conclusively demonstrated. Thus, the PS-R is the best characterized in regard to its ability to recognize PS on the surface of the apoptotic body/cell.…”

Section: Discussionmentioning

confidence: 99%

“…These data suggest that, as in macrophages, microtubules are involved in the engulfment of apoptotic bodies by stellate cells (Fadok and Chimini, 2001;Krahling et al, 1999). More importantly, nocodazole provided a tool to examine the importance of apoptotic body engulfment in COLIA1 and TGF-␤1 generation by the stellate cells.…”

Section: Discussionmentioning

confidence: 99%

“…Apoptotic bodies externalize PS, which is recognized as an "eat me" signal by the engulfing cell (Fadok and Chimini, 2001;Krahling et al, 1999). A variety of cell surface receptors have been implicated in recognizing this signal and in the engulfment process, including the PS-R, several scavenger receptors of both A and B classes, the LPS receptor CD14, and integrins of the ␣v␤3 or ␣v␤5 classes (Fadok and Chimini, 2001;Henson et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Externalized PS on the plasma membrane of the apoptotic bodies is recognized as an "engulfment signal" by the phagocytes Krahling et al, 1999). Because PS-R expression by phagocytes has been implicated in the engulfment process, we next determined whether LX-1 cells express this receptor.…”

Section: Is Engulfment Of Apoptotic Bodies By Lx-1 Microtubule Dependmentioning

confidence: 99%

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Apoptotic Body Engulfment by a Human Stellate Cell Line Is Profibrogenic

Canbay

Taimr

Torok

et al. 2003

Laboratory Investigation

380

274

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SUMMARY:Hepatocyte apoptosis and stellate cell activation are both features of chronic liver diseases, but a relationship between these events has not been explored. In macrophages, engulfment of apoptotic bodies induces expression of transforming growth factor-␤ (TGF-␤), a profibrogenic cytokine. We examined whether a similar response occurs in stellate cells. Fluorescently labeled hepatocyte apoptotic bodies were added to cultures of primary and immortalized human stellate cells. Stellate cells, but not hepatocytes, readily engulfed apoptotic bodies in a time-dependent manner as assessed by confocal microscopy. The activation of primary and immortalized human stellate cells after incubation with apoptotic bodies, as well as their fibrogenic activity, was indicated by an increase in ␣-smooth muscle actin (primary cells), TGF-␤1, and collagen ␣1(I) mRNA (primary and immortalized cells). The profibrogenic response was dependent upon apoptotic body engulfment, because nocodazole, a microtubule-inhibiting agent, blocked both the engulfment and the increase of TGF-␤1 and collagen ␣1(I) mRNA. As described in primary rodent stellate cells, up-regulation of collagen ␣1(I) mRNA was inhibited by a PI-3K inhibitor (LY294002) and a p38 mitogen-activated protein kinase inhibitor (SB203580) in LX-1 cells. In conclusion, these data support a model in which engulfment of hepatocyte apoptotic bodies by stellate cells leads to a fibrogenic response by eliciting a kinase-signaling pathway. (Lab Invest 2003, 83:655-663).L iver fibrosis is a cardinal feature of chronic liver injury. Indeed, despite the wide array of metabolic, genetic, viral, and cholestatic pathologies causing human liver injury, fibrosis is a common, if not generic, response of the liver to these injury processes. Extensive liver fibrosis results from the deposition and accumulation of type I collagen within the liver parenchyma and is recognized clinically as cirrhosis. The clinical complications of cirrhosis include portal hypertension and chronic liver failure. For many patients with advanced liver cirrhosis, the only viable treatment option is liver transplantation, highlighting the clinical severity of this fibrotic process. Insights into the mechanisms initiating and promoting liver fibrosis are, therefore, of broad scientific and clinical importance.Activated hepatic stellate cells have been established as the source of type I collagen in the liver (de Leeuw et al, 1984;Friedman et al, 1985;McGee and Patrick, 1972). Under basal conditions, hepatic stellate cells are in a quiescent state and function to store retinoids within the liver (Blomhoff et al, 1990;Geerts, 2001). However, upon activation, these cells undergo transformation, assuming a myofibroblast morphology and expressing smooth muscle actin (Ramadori et al, 1990;Schmitt-Graff et al, 1991). These activated stellate cells secrete collagen types I and III, the principle matrix protein responsible for the development of liver fibrosis and cirrhosis (Friedman, 2000;Kent et al, 1976). Over time, activ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Is Engulfment Of Apoptotic Bodies By Lx-1 Microtubule Dependmentioning

confidence: 99%

See 2 more Smart Citations

Apoptotic Body Engulfment by a Human Stellate Cell Line Is Profibrogenic

Canbay

Taimr

Torok

et al. 2003

Laboratory Investigation

380

274

View full text Add to dashboard Cite

show abstract

“…4 Blockade of apoptotic cell engulfment can be affected by the masking of PS through the pre-binding of annexin V to exposed PS on the apoptotic cell surface. 9 Immune pathologies attributed to the failure to promptly clear apoptotic cells, especially including chronic inflammation and autoimmunity characteristic of systemic lupus erythematosus and rheumatic diseases (see Savill et al 6 and Birge et al 8 and citations therein) may rather reflect deficiencies in apoptotic cell interactions and IAI.…”

Section: Open Questionsmentioning

confidence: 99%

Exploiting death: apoptotic immunity in microbial pathogenesis

Ucker

2016

Cell Death Differ

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Innate immunity typically is responsible for initial host responses against infections. Independently, nucleated cells that die normally as part of the physiological process of homeostasis in mammals (including humans) suppress immunity. Specifically, the physiological process of cell death (apoptosis) generates cells that are recognized specifically by viable cells of all types and elicit a profound transient suppression of host immunity (termed 'innate apoptotic immunity' (IAI)). IAI appears to be important normally for the maintenance of self-tolerance and for the resolution of inflammation. In addition, pathogens are able to take advantage of IAI through a variety of distinct mechanisms, to enable their proliferation within the host and enhance pathogenicity. For example, the protist pathogen Leishmania amazonensis, at its infective stage, mimics apoptotic cells by expressing apoptotic-like protein determinants on the cell surface, triggering immunosuppression directly. In contrast, the pathogenic bacterium Listeria monocytogenes triggers cell death in host lymphocytes, relying on those apoptotic cells to suppress host immune control and facilitate bacterial expansion. Finally, although the inhibition of apoptotic cell death is a common attribute of many viruses which facilitates their extended replication, it is clear that adenoviruses also reprogram the non-apoptotic dead cells that arise subsequently to manifest apoptotic-like immunosuppressive properties. These three instances represent diverse strategies used by microbial pathogens to exploit IAI, focusing attention on the potency of this facet of host immune control. Further examination of these cases will be revealing both of varied mechanisms of pathogenesis and the processes involved in IAI control.

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Modulation of the anti‐inflammatory effects of phosphatidylserine‐containing liposomes by PEGylation

Quan

Park

Kim

et al. 2017

J Biomedical Materials Res

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Inhibiting liposome uptake by macrophages using polyethylene glycol (PEG) surface modifications is a widely used approach for extending the half-life of liposomes circulating in the blood. However, the biological effects of PEGylated liposomes on macrophages have not yet been thoroughly investigated. The purpose of this study was to examine the effects of PEGylated phosphatidylserine-containing liposomes (PEG-PSLs) on the expression of two inflammation-associated cytokines, tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β), in the murine macrophage-like cell line RAW 264.7. Previous studies have demonstrated that PSLs inhibit TNF-α secretion and enhance TGF-β synthesis in macrophages by mimicking apoptotic cells. We found that PEGylation differentially affected the TNF-α and TGF-β levels. The PSL-mediated inhibitory effect on TNF-α secretion was enhanced by PEGylation, and PEG-PSLs decreased TGF-β levels compared with non-PEGylated PSLs. Fluorescence-activated cell sorting analysis demonstrated that 1% PEGylation disturbed the incorporation of PSLs into macrophages. The interference of uptake is thought to extend the binding interaction between PS to PS receptors for PSL-mediated inhibition of TNF-α expression. Together, these findings indicate that PEG-PSLs can prevent TNF-α secretion without increasing TGF-β levels in macrophages, and they support the potential clinical use of PEG-PSLs as anti-inflammatory agents with a relatively low potential to induce tissue fibrosis. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 1479-1486, 2017.

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Exposure of phosphatidylserine is a general feature in the phagocytosis of apoptotic lymphocytes by macrophages

Cited by 190 publications

References 18 publications

Apoptotic Body Engulfment by a Human Stellate Cell Line Is Profibrogenic

Apoptotic Body Engulfment by a Human Stellate Cell Line Is Profibrogenic

Exploiting death: apoptotic immunity in microbial pathogenesis

Modulation of the anti‐inflammatory effects of phosphatidylserine‐containing liposomes by PEGylation

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