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Efficient elimination of cells undergoing programmed cell death is crucial for normal tissue homeostasis and for the regulation of immune responses. This review examines unique signals presented by apoptotic cells and the mechanisms by which phagocytes recognize and respond to these signals to orchestrate the selective and rapid removal of apoptotic cells. Such unique signals include direct and indirect ‘eat-me’ markers on the apoptotic cell surface, the absence of ‘don't eat-me’ markers normally found on living cells and soluble ‘come-get-me’ signals secreted by apoptotic cells to attract phagocytes to sites of apoptotic cell death. Once apoptotic cells are identified, their uptake by phagocytes further depends on the molecular machinery highly conserved from Caenorhabditis elegans to mammals. 相似文献
3.
The clearance of apoptotic cells is important to maintain tissue homeostasis. The engulfment of apoptotic cells is performed by professional phagocytes, such as macrophages, and also by non-professional phagocytes, such as mesenchymal cells. Here, we show that vimentin, a cytoskeletal protein, functions as an engulfment receptor on neighboring phagocytes, which recognize O-linked β-N-acetylglucosamine (O-GlcNAc)-modified proteins from apoptotic cells as "eat me" ligands. Previously, we reported that vimentin possesses a GlcNAc-binding lectin-like property on cell surface. However, the physiological relevance of the surface localization and GlcNAc-binding property of vimentin remained unclear. In the present study, we observed that O-GlcNAc proteins from apoptotic cells interacted with the surface vimentin of neighboring phagocytes and that this interaction induced serine 71-phosphorylation and recruitment of vimentin to the cell surface of the neighboring phagocytes. Moreover, tetrameric vimentin that was disassembled by serine 71-phosphorylation possessed a GlcNAc-binding activity and was localized to the cell surface. We demonstrated our findings in vimentin-expressing common cell lines such as HeLa cells. Furthermore, during normal developmental processes, the phagocytic engulfment and clearance of apoptotic footplate cells in mouse embryos was mediated by the interaction of surface vimentin with O-GlcNAc proteins. Our results suggest a common mechanism for the clearance of apoptotic cells, through the interaction of surface vimentin with O-GlcNAc-modified proteins. 相似文献
4.
Engulfment of apoptotic cells by phagocytes is important throughout development and adult life. When phagocytes engulf apoptotic cells, they increase their cellular contents including cholesterol and phospholipids, but how the phagocytes respond to this increased load is poorly understood. Here, we identify one type of a phagocyte response, wherein the recognition of apoptotic cells triggers enhanced cholesterol efflux (to apolipoprotein A-I) from macrophages. Phosphatidylserine (PS) exposed on apoptotic cells was necessary and sufficient to stimulate the efflux response. A major mechanism for this enhanced efflux by macrophages was the upregulation of the mRNA and protein for ABCA1, a membrane transporter independently linked to cholesterol efflux as well as engulfment of apoptotic cells. This increase in phagocyte ABCA1 levels required the function of nuclear receptor LXRalpha/beta, a known regulator of cholesterol homeostasis in humans and mice. Taken together, these data reveal a "homeostatic program" initiated in phagocytes that include a proximal membrane signaling event initiated by PS recognition, a downstream signaling event acting through nuclear receptors, and an effector arm involving upregulation of ABCA1, in turn promoting reverse cholesterol transport from the phagocytes. These data also have implications for macrophage handling of contents derived from apoptotic versus necrotic cells in atherosclerotic lesions. 相似文献
5.
Cholesterol-induced apoptotic macrophages elicit an inflammatory response in phagocytes, which is partially attenuated by the Mer receptor 总被引:1,自引:0,他引:1
Li Y Gerbod-Giannone MC Seitz H Cui D Thorp E Tall AR Matsushima GK Tabas I 《The Journal of biological chemistry》2006,281(10):6707-6717
Macrophage apoptosis and the ability of phagocytes to clear these apoptotic cells are important processes in advanced atherosclerosis. Phagocytic clearance not only disposes of dead cells but usually elicits an anti-inflammatory response. To study this process in a model of advanced lesional macrophage death, macrophages rendered apoptotic by free cholesterol loading (FC-AMs) were incubated briefly with fresh macrophages ("phagocytes"). FC-AMs were promptly ingested by the phagocytes, which was dependent upon actin polymerization and the phagocyte Mer receptor. Surprisingly, this brief exposure to FC-AMs triggered a modest proinflammatory response in the phagocytes: tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-1beta were induced, whereas the levels of transforming growth factor-beta and IL-10 were not increased. This response required cell contact between the FC-AMs and phagocytes but not FC-AM ingestion. TNF-alpha and IL-1beta induction required one or more proteins on the FC-AM surface and was dependent on signaling through extracellular signal-regulated kinase-1/2 mitogen-activated protein kinase and nuclear factor-kappaB in the phagocytes. TNF-alpha production was markedly greater when Mer-defective phagocytes were used, indicating that Mer attenuated the inflammatory response. Interestingly, a more typical anti-inflammatory response was elicited when phagocytes were exposed to macrophages rendered apoptotic by oxidized low density lipoprotein or UV radiation. Thus, the proinflammatory milieu of advanced atherosclerotic lesions may be promoted, or at least not dampened, by contact between FC-induced apoptotic macrophages and neighboring phagocytes prior to apoptotic cell ingestion. 相似文献
6.
Phagocytosis of apoptotic cells and the resolution of inflammation 总被引:10,自引:0,他引:10
Clearance of apoptotic cells by phagocytic cells plays a significant role in the resolution of inflammation, protecting tissue from harmful exposure to the inflammatory and immunogenic contents of dying cells. Apoptosis induces cell surface changes that are important for recognition and engulfment of cells by phagocytes. These changes include alterations in surface sugars, externalization of phosphatidylserine and qualitative changes in the adhesion molecule ICAM-3. Several studies have contributed to clarify the role of the receptors on the surface of phagocytes that are involved in apoptotic cell clearance. The phagocytic removal of apoptotic cells does not elicit pro-inflammatory responses; in contrast, apoptotic cell engulfment appears to activate signals that suppress release of pro-inflammatory cytokines. Therefore, clearance of apoptotic leucocytes is implicated in the resolution of inflammation and mounting evidence suggests that defective clearance of apoptotic cells contributes to inflammatory and autoimmune diseases. Defining the ligands on apoptotic cells and the corresponding receptors on phagocytes with which they engage, is likely to lead to the development of novel anti-inflammatory pro-resolution drugs. In this article, we will review the recognition and signaling mechanisms involved in the phagocytosis of apoptotic cells as well as the role of endogenous compounds that play a relevant role in the modulation of inflammation. We will also discuss what is currently known about diseases that may reflect impaired phagocytosis and the consequences on inflammation and immune responses. 相似文献
7.
Recognition of phosphatidylserine (PtdSer) is essential for engulfment of apoptotic cells by mammalian phagocytes. Engagement of a new phosphatidylserine-specific receptor (PtdSerR) appears to be necessary for uptake of apoptotic cells. Many other mammalian receptors have been described to function in the clearance of apoptotic cells. The emerging picture is that many of these receptors may provide the strong adhesion needed to increase the likelihood of contact between the PtdSerR and its phospholipid ligand, which is required for uptake. Furthermore, stimulation of this receptor on different types of phagocytes by apoptotic cells, PtdSer-containing liposomes or an IgM monoclonal anti-PtdSer antibody initiates release of TGFbeta, known to be involved in the anti-inflammatory effects of apoptotic cells. Although highly homologous genes exist in C. elegans and Drosophila melanogaster, their role in engulfment of apoptotic cells remains to be determined. 相似文献
8.
Stach CM Turnay X Voll RE Kern PM Kolowos W Beyer TD Kalden JR Herrmann M 《Cell death and differentiation》2000,7(10):911-915
Exposure of phosphatidylserine on the outer leaflet of the cytoplasmic membrane is an early event during apoptotic cell death and serves as a recognition signal for phagocytes. Usually the clearance of apoptotic cells does not initiate inflammation or immune response. We investigated the immune response in Balb/c mice towards apoptotic human T-cells. Animals injected with apoptotic cells showed significantly reduced humoral immune responses, especially Th1-dependent IgG2a titres, compared to controls immunised with viable cells. However, treatment of apoptotic cells with annexin V (AxV) significantly increased the humoral immune response. AxV binds with high affinity to anionic phospholipids and as a result interferes with the phosphatidylserine recognition by phagocytes. Our results indicate that AxV treatment may be used to increase the efficiency of apoptotic cell-based vaccines, e.g. some tumour vaccines. 相似文献
9.
Currently used assays for the quantification of apoptotic cells uptake by phagocytes have several methodological problems. Our assay overcomes some of these problems. As a source of apoptotic cells we used peripheral blood lymphocytes obtained from the patients with chronic lymphoblast leukaemia. Apoptosis was induced by incubating cells with cycloheximide for up to 24 h. The assay was performed in suspension of peripheral blood mononuclear cells. For the visualisation of the phagocytes and phagocyted cells and discrimination of phagocyted from bound apoptotic cells we used Acridine orange/Ethidium bromide double staining. Here we offer a simple test which enables reliable measurement and it can show the difference of phagocytic potential between different individuals. 相似文献
10.
Kuraishi T Manaka J Kono M Ishii H Yamamoto N Koizumi K Shiratsuchi A Lee BL Higashida H Nakanishi Y 《Experimental cell research》2007,313(3):500-510
Apoptotic cell phagocytosis is initiated through the specific interaction between markers for phagocytosis present at the surface of targets and their receptors of phagocytes. Although many molecules have been proposed to be phagocytosis markers and receptors in mammals, information as to the identity of those molecules is limited for invertebrate animals. Calreticulin, a molecular chaperone that functions in the lumen of the endoplasmic reticulum, was recently reported to be the second general marker, the membrane phospholipid phosphatidylserine being the first, for mammalian apoptotic cells to be recognized by phagocytes. We here asked whether or not calreticulin serves as a marker for phagocytosis in Drosophila. Phagocytosis of apoptotic S2 cells by Drosophila hemocyte-derived l(2)mbn cells, which we previously showed to occur independent of phosphatidylserine, was inhibited by the addition of anti-calreticulin antibody. This inhibition was observed when the target cells, but not phagocytes, were pre-incubated with the antibody. In addition, RNA interference-mediated reduction of calreticulin expression in apoptotic S2 cells, but not in l(2)mbn cells, reduced the level of phagocytosis. An immunocytochemical analysis revealed that calreticulin is widely distributed at the surface of viable S2 cells. After the induction of apoptosis, cell surface calreticulin seemed to form aggregates, with no change in its amount. Furthermore, in embryos of a mutant Drosophila strain that expresses calreticulin at a reduced level, the level of phagocytosis of apoptotic cells was about a half of that observed in embryos of a wild-type strain. These results collectively indicate that calreticulin is the first molecule to be identified as a marker for phagocytosis of apoptotic cells by Drosophila phagocytes. 相似文献
11.
Phagocytosis of apoptotic cells 总被引:1,自引:0,他引:1
Removal of apoptotic cells by phagocytes plays an important role in many biological processes, including embryological development and tissue remodelling. In addition, it has become apparent that one of the key mechanisms for the successful resolution of inflammation is the orchestrated clearance of apoptotic inflammatory cells by phagocytes (e.g., macrophages and dendritic cells) and other cells known to have phagocytic capacity (e.g., hepatocytes, endothelial cells, epithelial cells, etc.). Furthermore, phagocytosis of apoptotic cells is an active and highly regulated process that not only serves to remove potentially histotoxic cells from the inflammatory milieu, but also directs the phenotype of the phagocytic cell to be anti-inflammatory. Convincing evidence has been presented that reduced or dysregulated phagocytosis of apoptotic cells contributes to the development and propagation of inflammatory disorders. Conversely, enhanced phagocytosis of apoptotic cells may be exploited for therapeutic gain. Indeed, powerful anti-inflammatory drugs such as the glucocorticoids have been shown to augment clearance of apoptotic cells which may contribute to their therapeutic effectiveness. In this chapter, we describe methods for studying phagocytosis of apoptotic cells. 相似文献
12.
Intact CD3-specific antibody transiently depletes large numbers of T cells and subsequently induces long-term immune tolerance. The underlying mechanisms for the systemic tolerance, however, remain unclear. We show here that treatment of normal mice with intact antibody to CD3 increases systemic transforming growth factor-beta (TGF-beta) produced by phagocytes exposed to apoptotic T cells. Among the phagocytes, macrophages and immature dendritic cells (iDCs) secrete TGF-beta upon ingestion of apoptotic T cells, which induces CD4+Foxp3+ regulatory T cells in culture and contributes to immune tolerance mediated by CD3-specific antibody in vivo. In accordance with these results, depletion of macrophages and iDCs not only abrogates CD3-specific antibody-mediated prevention of myelin oligodendrocyte glycoprotein-induced acute experimental autoimmune encephalomyelitis (EAE), but also reverses the therapeutic effects of antibody to CD3 on established disease in a model of relapsing-remitting EAE. Thus, CD3-specific antibody-induced immune tolerance is associated with TGF-beta production in phagocytes involved in clearing apoptotic T cells, which suggests that apoptosis is linked to active suppression in immune tolerance. 相似文献
13.
Differences between the clearance of apoptotic cells by professional and non-professional phagocytes 总被引:1,自引:0,他引:1
Both professional and non-professional phagocytes [1] participate in clearing the massive numbers of cells that undergo apoptosis during animal development [2], but it is not known how they divide this task. Using time-lapse recordings of cells in culture, we show that professional phagocytes (brain macrophages or microglia) are highly motile, ingest apoptotic cells immediately, and digest them quickly. Non-professionals such as BHK and lens epithelial cells are sessile, often recognize apoptotic cells as soon as they die by showing characteristic palpating movements, but delay ingestion until several hours later. By pre-ageing apoptotic cells, we show that this delay is because the apoptotic cells must undergo further changes before non-professionals can ingest them. The difference was also apparent in vivo, using immunofluorescence and electron microscopy of the developing central nervous system. This arrangement favours prompt clearance by professionals if present in adequate numbers; if they are scarce, however, non-professional bystanders will reluctantly clear the apoptotic cells. 相似文献
14.
Apoptosis: the importance of being eaten 总被引:11,自引:0,他引:11
In vivo, cells undergoing apoptosis are usually recognised and swiftly ingested by macrophages or neighbouring cells acting as semi-professional phagocytes. This review debates evidence that the contents of apoptotic cells represent a danger to the organism, being capable of injuring tissue directly or triggering autoimmune responses, concluding that phagocytic clearance of intact apoptotic cells is a safe disposal route. Indeed, new data suggest that, in certain circumstances, phagocytes ingesting apoptotic cells may actively downregulate inflammatory and immune responses. Consequently, increasing evidence that there may be factors capable of perturbing safe clearance of apoptotic cells in vivo suggests that failure of this process may be a hitherto unrecognised pathogenetic factor in inflammatory and autoimmune diseases. New treatments designed to promote safe phagocytic clearance of dying cells can be anticipated, and it may even prove possible to eliminate unwanted cells by inducing appearance of cell surface 'eat me' signals. 相似文献
15.
Boris Shklyar Flonia Levy-Adam Ketty Mishnaevski Estee Kurant 《Molecular and cellular biology》2013,33(16):3191-3201
Clearance of apoptotic cells by phagocytic neighbors is crucial for normal development of multicellular organisms. However, how phagocytes discriminate between healthy and dying cells remains poorly understood. We focus on glial phagocytosis of apoptotic neurons during development of the Drosophila central nervous system. We identified phosphatidylserine (PS) as a ligand on apoptotic cells for the phagocytic receptor Six Microns Under (SIMU) and report that PS alone is not sufficient for engulfment. Our data reveal that, additionally to PS exposure, caspase activity is required for clearance of apoptotic cells by phagocytes. Here we demonstrate that SIMU recognizes and binds PS on apoptotic cells through its N-terminal EMILIN (EMI), Nimrod 1 (NIM1), and NIM2 repeats, whereas the C-terminal NIM3 and NIM4 repeats control SIMU affinity to PS. Based on the structure-function analysis of SIMU, we discovered a novel mechanism of internal inhibition responsible for differential affinities of SIMU to its ligand which might prevent elimination of living cells exposing PS on their surfaces. 相似文献
16.
Clearance of apoptotic cells by phagocytes 总被引:3,自引:0,他引:3
Phagocytic clearance of apoptotic cells may be considered to consist of four distinct steps: accumulation of phagocytes at the site where apoptotic cells are located; recognition of dying cells through a number of bridge molecules and receptors; engulfment by a unique uptake process; and processing of engulfed cells within phagocytes. Here, we will discuss these individual steps that collectively are essential for the effective removal of apoptotic cells. This will illustrate our relative lack of knowledge about the initial attraction signals, the specific mechanisms of engulfment and processing in comparison to the extensive literature on recognition mechanisms. There is now mounting evidence that clearance defects are responsible for chronic inflammatory disease and contribute to autoimmunity. Therefore, a better understanding of all aspects of the clearance process is required before it can truly be manipulated for therapeutic gain. 相似文献
17.
Christopher D Gregory Adriano G Rossi Irini Bournazou Lihui Zhuang Jorine JLP Willems 《Cell Adhesion & Migration》2011,5(4):293-297
An expanding body of evidence demonstrates that cells undergoing apoptosis send out a selection of molecular navigational signals including proteins, lipids and nucleotides that serve to recruit phagocytes to the dying targets, which are subsequently engulfed and removed. This homeostatic process is essentially non-phlogistic, contrasting markedly with the acute inflammatory responses elicited in phagocytes by damaging or infectious agents. The “professional” scavengers of apoptotic cells are mononuclear phagocytes—the macrophages—and sites of high-rate apoptosis are clearly characterized by macrophages associated with the apoptotic cells. By contrast, members of the other class of professional phagocytes—the granulocytes—are not recruited to sites of apoptosis as a direct consequence of the cell-death program. Indeed, recent work indicates that apoptotic cells release a mixture of migratory cues to leukocytes in order to selectively attract mononuclear phagocytes but not granulocytes through functional balancing of positive and negative signals. Here we discuss these molecular mechanisms that not only serve as migratory cues but also may activate responding phagocytes to engulf apoptotic cells effectively. Finally, we speculate upon new therapeutic opportunities these mechanisms offer for a range of pathological conditions, including inflammatory disorders and cancer.Key words: apoptosis, migration, chemotaxis, macrophage, monocyte, granulocyte, phagocytosis, lactoferrin, ATP, fractalkine 相似文献
18.
Loss of phospholipid asymmetry and surface exposure of phosphatidylserine is required for phagocytosis of apoptotic cells by macrophages and fibroblasts 总被引:27,自引:0,他引:27
Fadok VA de Cathelineau A Daleke DL Henson PM Bratton DL 《The Journal of biological chemistry》2001,276(2):1071-1077
Removal of apoptotic cells during tissue remodeling or resolution of inflammation is critical to the restoration of normal tissue structure and function. During apoptosis, early surface changes occur, which trigger recognition and removal by macrophages and other phagocytes. Loss of phospholipid asymmetry results in exposure of phosphatidylserine (PS), one of the surface markers recognized by macrophages. However, a number of receptors have been reported to mediate macrophage recognition of apoptotic cells, not all of which bind to phosphatidylserine. We therefore examined the role of membrane phospholipid symmetrization and PS externalization in uptake of apoptotic cells by mouse macrophages and human HT-1080 fibrosarcoma cells by exposing them to cells that had undergone apoptosis without loss of phospholipid asymmetry. Neither mouse macrophages nor HT-1080 cells recognized or engulfed apoptotic targets that failed to express PS, in comparison to PS-expressing apoptotic cells. If, however, their outer leaflets were repleted with the l-, but not the d-, stereoisomer of sn-1,2-PS by liposome transfer, engulfment by both phagocytes was restored. These observations directly demonstrate that loss of phospholipid asymmetry and PS expression is required for phagocyte engulfment of apoptotic cells and imply a critical, if not obligatory, role for PS recognition in the uptake process. 相似文献
19.
Monks J Rosner D Geske FJ Lehman L Hanson L Neville MC Fadok VA 《Cell death and differentiation》2005,12(2):107-114
Clearance of apoptotic cells is critical to tissue homeostasis and resolution of inflammatory lesions. Macrophages are known to remove dying cells and release anti-inflammatory mediators in response; however, many cells traditionally thought of as poor phagocytes can mediate this function as well. In the lactating mammary gland following weaning, alveolar epithelial cell death is massive, yet the gland involutes rapidly, attaining its prepregnancy state in a matter of days. We found histologic evidence of apoptotic cell phagocytosis by viable mammary epithelial cells (MEC) in the involuting mouse mammary gland. Cultured MEC were able to engulf apoptotic cells in vitro, utilizing many of the same receptors used by macrophages, including the phosphatidylserine receptor (PSR), CD36, the vitronectin receptor alpha(v)beta3, and CD91. In addition, MEC, like macrophages, produced TGFbeta in response to stimulation of the PSR by apoptotic cells or the anti-PSR ab 217G8E9, and downregulated endotoxin-stimulated proinflammatory cytokine production. These data support the hypothesis that amateur phagocytes play a significant role in apoptotic cell clearance and its regulation of inflammation. 相似文献
20.
Ok-Hee Kim Geun-Hyung Kang June Hur Jinwook Lee YunJae Jung In-Sun Hong Hookeun Lee Seung-Yong Seo Dae Ho Lee Cheol Soon Lee In-Kyu Lee Susan Bonner-Weir Jongsoon Lee Young Joo Park Hyeonjin Kim Steven E. Shoelson Byung-Chul Oh 《Cell death and differentiation》2022,29(7):1423
Apoptotic cells are rapidly engulfed and removed by phagocytes after displaying cell surface eat-me signals. Among many phospholipids, only phosphatidylserine (PS) is known to act as an eat-me signal on apoptotic cells. Using unbiased proteomics, we identified externalized phosphatidylinositides (PIPs) as apoptotic eat-me signals recognized by CD14+ phagocytes. Exofacial PIPs on the surfaces of early and late-apoptotic cells were observed in patches and blebs using anti-PI(3,4,5)P3 antibody, AKT- and PLCδ PH-domains, and CD14 protein. Phagocytosis of apoptotic cells was blocked either by masking exofacial PIPs or by CD14 knockout in phagocytes. We further confirmed that exofacial PIP+ thymocytes increased dramatically after in vivo irradiation and that exofacial PIP+ cells represented more significant populations in tissues of Cd14−/− than WT mice, especially after induction of apoptosis. Our findings reveal exofacial PIPs to be previously unknown cell death signals recognized by CD14+ phagocytes.Subject terms: Phospholipids, Cell death and immune response 相似文献