Surface expression of phosphatidylserine on macrophages is required for phagocytosis of apoptotic thymocytes

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

doi:10.1038/sj.cdd.4400690

Cited by 159 publications

(141 citation statements)

References 46 publications

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“…It will be interesting to examine whether any other molecules work as phosphatidylserine receptors. Some non-apoptotic T or B cells 25,26 as well as macrophages 27 have been reported to bind annexin V. Here, we showed that the cells expressing Tim1 or Tim4 associated with exosomes that carried exposed PS. Activated Th2 cells and B cells express Tim1 28,29 , while the resident macrophages express Tim4, suggesting that the nonapoptotic annexin V-binding cells are those that express Tim1 or Tim4.…”

mentioning

confidence: 53%

Identification of Tim4 as a phosphatidylserine receptor

Miyanishi

Tada

Koike

et al. 2007

Nature

1,021

903

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In programmed cell death, a large number of cells undergo apoptosis, and are engulfed by macrophages to avoid the release of noxious materials from the dying cells 1,2 . In definitive erythropoiesis, nuclei are expelled from erythroid precursor cells and are engulfed by macrophages. Phosphatidylserine is exposed on the surface of apoptotic cells 3 and on the nuclei expelled from erythroid precursor cells 4 ; it works as an 'eat me' signal for phagocytes 5,6 . Phosphatidylserine is also expressed on the surface of exosomes involved in intercellular signalling 7 . Here we established a library of hamster monoclonal antibodies against mouse peritoneal macrophages, and found an antibody that strongly inhibited the phosphatidylserine-dependent engulfment of apoptotic cells. The antigen recognized by the antibody was identified by expression cloning as a type I transmembrane protein called Tim4 (T-cell immunoglobulin-and mucin-domain-containing molecule; also known as Timd4) 8 . Tim4 was expressed in Mac1 1 cells in various mouse tissues, including spleen, lymph nodes and fetal liver. Tim4 bound apoptotic cells by recognizing phosphatidylserine via its immunoglobulin domain. The expression of Tim4 in fibroblasts enhanced their ability to engulf apoptotic cells. When the anti-Tim4 monoclonal antibody was administered into mice, the engulfment of apoptotic cells by thymic macrophages was significantly blocked, and the mice developed autoantibodies. Among the other Tim family members, Tim1, but neither Tim2 nor Tim3, specifically bound phosphatidylserine. Tim1-or Tim4-expressing Ba/F3 B cells were bound by exosomes via phosphatidylserine, and exosomes stimulated the interaction between Tim1 and Tim4. These results indicate that Tim4 and Tim1 are phosphatidylserine receptors for the engulfment of apoptotic cells, and may also be involved in intercellular signalling in which exosomes are involved.Caspase-activated DNase (CAD)-deficient cells do not undergo apoptotic DNA fragmentation, but their DNA is degraded in phagocytes after they are engulfed 9 . We used this knowledge to assay the

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mentioning

confidence: 53%

Identification of Tim4 as a phosphatidylserine receptor

Miyanishi

Tada

Koike

et al. 2007

Nature

1,021

903

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“…67 This PS exposed on the phagocyte surface is required in the phagocytosis process, since treating macrophages with annexin is as effective as treating apoptotic lymphocytes in blocking the engulfment process. 84 The engulfment process thus seems to require interactions between PS-exposing membranes on both the engulfing and target cells, interactions that are not required for engulfment of other, non-PS-exposing particles by the same phagocytes.…”

Section: Cell Death and Differentiationmentioning

confidence: 99%

Phosphatidylserine, a death knell

2001

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Virtually every cell in the body restricts phosphatidylserine (PS) to the inner leaflet of the plasma membrane by energydependent transport from the outer to the inner leaflet of the bilayer. Apoptotic cells of all types rapidly randomize the asymmetric distribution, bringing PS to the surface where it serves as a signal for phagocytosis. A myriad of phagocyte receptors have been implicated in the recognition of apoptotic cells, among them a PS receptor, yet few ligands other than PS have been identified on the apoptotic cell surface. Since apoptosis and the associated exposure of PS on the cell surface is probably over 600 million years old, it is not surprising that evolution has appropriated aspects of this process for specialized purposes such as blood coagulation, membrane fusion and erythrocyte differentiation. Failure to efficiently remove apoptotic cells may contribute to inflammatory responses and autoimmune diseases resulting from chronic, inappropriate exposure of PS. Cell Death and Differentiation (2001) 8, 551 ± 563.

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“…For annexin V staining, cells were resuspended in annexin V staining buffer (10 mM HEPES/NaOH, pH 7.4, 140 mM NaCl, 2.5 mM CaCl 2 ) before staining with PE-conjugated annexin V (BD PharMingen). Propidium iodide was added before flow cytometry to gate out dead cells (19). As negative controls for all annexin V staining, cells were extensively washed in Ca 2ϩ -free PBS before adding annexin V.…”

Section: Flow Cytometrymentioning

confidence: 99%

“…Following HIV-1 infection, T cells are highly susceptible to programmed cell death, and peak levels of T cell apoptosis correlate with high levels of virus replication (18). Furthermore, mature macrophages constitutively express PS in the outer leaflet of their plasma membranes (19), although their precursors, monocytes, do not (20). Therefore, HIVinfected T cells and macrophages would be expected to have elevated levels of surface PS, and HIV-1 particles produced by these cells would have PS incorporated into the outer leaflet of their envelopes.…”

mentioning

confidence: 99%

Phosphatidylserine on HIV Envelope Is a Cofactor for Infection of Monocytic Cells

Callahan¹,

Popernack

Tsutsui³

et al. 2003

The Journal of Immunology

126

116

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HIV-1 is an enveloped retrovirus that acquires its outer membrane as the virion exits the cell. Because of the association of apoptosis with the progression of AIDS, HIV-1-infected T cells or macrophages might be expected to express elevated levels of surface phosphatidylserine (PS), a hallmark of programmed cell death. Virions produced by these cells would also be predicted to have PS on the surface of their envelopes. In this study, data are presented that support this hypothesis and suggest that PS is required for macrophage infection. The PS-specific protein annexin V was used to enrich for virus particles and to inhibit HIV-1 replication in primary macrophages, but not T cells. HIV-1 replication was also significantly inhibited with vesicles consisting of PS, but not phosphatidylcholine. PS is specifically required for HIV-1 infection because viruses pseudotyped with vesicular stomatitis virus G and amphotropic murine leukemia virus envelopes were not inhibited by PS vesicles or annexin V. These data indicate that PS is an important cofactor for HIV-1 infection of macrophages.

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Surface expression of phosphatidylserine on macrophages is required for phagocytosis of apoptotic thymocytes

Cited by 159 publications

References 46 publications

Identification of Tim4 as a phosphatidylserine receptor

Identification of Tim4 as a phosphatidylserine receptor

Phosphatidylserine, a death knell

Phosphatidylserine on HIV Envelope Is a Cofactor for Infection of Monocytic Cells

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