Home LiteratureArticle Details
PMID: 11706053 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells.

The Journal of cell biology ·Vol. 155 ·No. 4 ·2001-11-12 ·Pages 649-59

Hoffmann PR, deCathelineau AM, Ogden CA, Leverrier Y, Bratton DL, Daleke DL, Ridley AJ, Fadok VA, Henson PM

Abstract

Efficient phagocytosis of apoptotic cells is important for normal tissue development, homeostasis, and the resolution of inflammation. Although many receptors have been implicated in the clearance of apoptotic cells, the roles of these receptors in the engulfment process have not been well defined. We developed a novel system to distinguish between receptors involved in tethering of apoptotic cells versus those inducing their uptake. Our results suggest that regardless of the receptors engaged on the phagocyte, ingestion does not occur in the absence of phosphatidylserine (PS). Further, recognition of PS was found to be dependent on the presence of the PS receptor (PSR). Both PS and anti-PSR antibodies stimulated membrane ruffling, vesicle formation, and "bystander" uptake of cells bound to the surface of the phagocyte. We propose that the phagocytosis of apoptotic cells requires two events: tethering followed by PS-stimulated, PSR-mediated macropinocytosis.

MeSH Terms
3T3 Cells Animals Antibodies, Monoclonal/immunology Apoptosis/immunology Cell Membrane Cells, Cultured Humans Jumonji Domain-Containing Histone Demethylases Mice Monocytes/cytology,immunology Phagocytes/immunology Phosphatidylserines/immunology Pinocytosis/immunology Receptors, Cell Surface/immunology cdc42 GTP-Binding Protein/immunology rac1 GTP-Binding Protein/immunology rhoA GTP-Binding Protein/immunology
Chemicals
Antibodies, Monoclonal Phosphatidylserines Ptdsr protein, mouse Receptors, Cell Surface phosphatidylserine receptor JMJD6 protein, human Jumonji Domain-Containing Histone Demethylases cdc42 GTP-Binding Protein rac1 GTP-Binding Protein rhoA GTP-Binding Protein
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Hoffmann P R
Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206, USA.
deCathelineau A M
Ogden C A
Leverrier Y
Bratton D L
Daleke D L
Ridley A J
Fadok V A
Henson P M
References (70)
70 references, click to expand
  1. The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors.
    Cell. 1992 Aug 7;70(3):389-99 PMID: 1643657
  2. Cell death: the significance of apoptosis.
    Int Rev Cytol. 1980;68:251-306 PMID: 7014501
  3. Requirement for Rho GTPases and PI 3-kinases during apoptotic cell phagocytosis by macrophages.
    Curr Biol. 2001 Feb 6;11(3):195-9 PMID: 11231156
  4. C1q and mannose binding lectin engagement of cell surface calreticulin and CD91 initiates macropinocytosis and uptake of apoptotic cells.
    J Exp Med. 2001 Sep 17;194(6):781-95 PMID: 11560994
  5. Involvement of the epidermal growth factor receptor in the invasion of cultured mammalian cells by Salmonella typhimurium.
    Nature. 1992 Jun 18;357(6379):588-9 PMID: 1608468
  6. Human CD14 mediates recognition and phagocytosis of apoptotic cells.
    Nature. 1998 Apr 2;392(6675):505-9 PMID: 9548256
  7. Different populations of macrophages use either the vitronectin receptor or the phosphatidylserine receptor to recognize and remove apoptotic cells.
    J Immunol. 1992 Dec 15;149(12):4029-35 PMID: 1281199
  8. Multiple systems for recognition of apoptotic lymphocytes by macrophages.
    Mol Biol Cell. 1997 May;8(5):767-78 PMID: 9168465
  9. CED-1 is a transmembrane receptor that mediates cell corpse engulfment in C. elegans.
    Cell. 2001 Jan 12;104(1):43-56 PMID: 11163239
  10. The small GTP-binding protein rac regulates growth factor-induced membrane ruffling.
    Cell. 1992 Aug 7;70(3):401-10 PMID: 1643658
  11. The coated pit and macropinocytic pathways serve distinct endosome populations.
    J Cell Biol. 1994 Mar;124(5):689-703 PMID: 8120092
  12. An assay for the quantitative measurement of in vitro phagocytosis of early apoptotic thymocytes by murine resident peritoneal macrophages.
    J Immunol Methods. 1999 Mar 4;223(2):237-48 PMID: 10089102
  13. Scavenger receptors in innate immunity.
    Curr Opin Immunol. 1996 Feb;8(1):20-8 PMID: 8729442
  14. Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells, induces the maturation of immunostimulatory dendritic cells.
    J Exp Med. 2000 Feb 7;191(3):423-34 PMID: 10662788
  15. A 125/115-kDa cell surface receptor specific for vitronectin interacts with the arginine-glycine-aspartic acid adhesion sequence derived from fibronectin.
    Proc Natl Acad Sci U S A. 1985 Sep;82(17):5766-70 PMID: 2412224
  16. Differences between the clearance of apoptotic cells by professional and non-professional phagocytes.
    Curr Biol. 2000 Jul 13;10(14):857-60 PMID: 10899007
  17. M-CSF-induced macropinocytosis increases solute endocytosis but not receptor-mediated endocytosis in mouse macrophages.
    J Cell Sci. 1992 Aug;102 ( Pt 4):867-80 PMID: 1429898
  18. Identification of a domain (155-183) on CD36 implicated in the phagocytosis of apoptotic neutrophils.
    J Biol Chem. 1996 Jun 28;271(26):15381-5 PMID: 8663130
  19. Complement dependent immune phagocytosis. I. Requirements for C'1, C'4, C'2, C'3.
    Exp Cell Res. 1968 Jul;51(1):45-67 PMID: 5661952
  20. Promotion of the uptake of PS liposomes and apoptotic cells by a product of growth arrest-specific gene, gas6.
    J Biochem. 2000 Mar;127(3):411-7 PMID: 10731712
  21. Role of class B scavenger receptor type I in phagocytosis of apoptotic rat spermatogenic cells by Sertoli cells.
    J Biol Chem. 1999 Feb 26;274(9):5901-8 PMID: 10026214
  22. The enzymatic synthesis of phosphatidylserine and purification by CM-cellulose column chromatography.
    Biochim Biophys Acta. 1977 Jul 20;488(1):36-42 PMID: 560868
  23. Phorbol esters stimulate macropinocytosis and solute flow through macrophages.
    J Cell Sci. 1989 Sep;94 ( Pt 1):135-42 PMID: 2613767
  24. Genetic control of programmed cell death in the Caenorhabditis elegans hermaphrodite germline.
    Development. 1999 Feb;126(5):1011-22 PMID: 9927601
  25. Apoptosis: the importance of being eaten.
    Cell Death Differ. 1998 Jul;5(7):563-8 PMID: 10200510
  26. Lectin-like oxidized low-density lipoprotein receptor 1 mediates phagocytosis of aged/apoptotic cells in endothelial cells.
    Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9535-40 PMID: 9689115
  27. A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo.
    J Exp Med. 2000 Aug 7;192(3):359-66 PMID: 10934224
  28. Phagocyte recognition of cells undergoing apoptosis.
    Immunol Today. 1993 Mar;14(3):131-6 PMID: 8385467
  29. Requirement of CDC42 for Salmonella-induced cytoskeletal and nuclear responses.
    Science. 1996 Dec 20;274(5295):2115-8 PMID: 8953049
  30. Influence of epidermal growth factor (EGF) on ruffling activity, pinocytosis and proliferation of cultivated human glia cells.
    Exp Cell Res. 1976 Dec;103(2):295-302 PMID: 1001364
  31. Early redistribution of plasma membrane phosphatidylserine is a general feature of apoptosis regardless of the initiating stimulus: inhibition by overexpression of Bcl-2 and Abl.
    J Exp Med. 1995 Nov 1;182(5):1545-56 PMID: 7595224
  32. Uncoupling of membrane ruffling and pinocytosis during Ras signal transduction.
    J Biol Chem. 1997 Apr 18;272(16):10337-40 PMID: 9099668
  33. alphavbeta5 integrin recruits the CrkII-Dock180-rac1 complex for phagocytosis of apoptotic cells.
    Nat Cell Biol. 2000 Dec;2(12):899-905 PMID: 11146654
  34. Macrophage recognition of cells undergoing programmed cell death (apoptosis).
    Immunology. 1985 Oct;56(2):351-8 PMID: 3876985
  35. Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease.
    Nature. 1992 Oct 22;359(6397):693-9 PMID: 1436033
  36. Regulation of phosphatidylserine exposure and phagocytosis of apoptotic T lymphocytes.
    Cell Death Differ. 1999 Mar;6(3):262-70 PMID: 10200577
  37. Surfactant protein A enhances alveolar macrophage phagocytosis of apoptotic neutrophils.
    J Immunol. 2001 Feb 15;166(4):2727-33 PMID: 11160338
  38. Cell surface exposure of phosphatidylserine during apoptosis is phylogenetically conserved.
    Apoptosis. 1998;3(1):9-16 PMID: 14646513
  39. Macrophage colony-stimulating factor (rM-CSF) stimulates pinocytosis in bone marrow-derived macrophages.
    J Exp Med. 1989 Nov 1;170(5):1635-48 PMID: 2681516
  40. Distinct endocytotic pathways in epidermal growth factor-stimulated human carcinoma A431 cells.
    J Cell Biol. 1989 Dec;109(6 Pt 1):2731-9 PMID: 2556406
  41. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-beta, PGE2, and PAF.
    J Clin Invest. 1998 Feb 15;101(4):890-8 PMID: 9466984
  42. Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis.
    Blood. 1994 Sep 1;84(5):1415-20 PMID: 8068938
  43. Recognition of apoptotic cells by human macrophages: inhibition by a monocyte/macrophage-specific monoclonal antibody.
    Eur J Immunol. 1994 Nov;24(11):2625-32 PMID: 7525298
  44. Macropinocytosis.
    Trends Cell Biol. 1995 Nov;5(11):424-8 PMID: 14732047
  45. Recognition of oxidatively damaged and apoptotic cells by an oxidized low density lipoprotein receptor on mouse peritoneal macrophages: role of membrane phosphatidylserine.
    Proc Natl Acad Sci U S A. 1995 Feb 28;92(5):1396-400 PMID: 7877989
  46. The molecular mechanism of programmed cell death in C. elegans.
    Ann N Y Acad Sci. 1999;887:92-104 PMID: 10668467
  47. Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages.
    J Immunol. 1992 Apr 1;148(7):2207-16 PMID: 1545126
  48. A receptor for phosphatidylserine-specific clearance of apoptotic cells.
    Nature. 2000 May 4;405(6782):85-90 PMID: 10811223
  49. Altered lipid packing identifies apoptotic thymocytes.
    Immunol Lett. 1993 Jun;36(3):283-8 PMID: 8370600
  50. A common set of engulfment genes mediates removal of both apoptotic and necrotic cell corpses in C. elegans.
    Nat Cell Biol. 2000 Dec;2(12):931-7 PMID: 11146658
  51. The 94- to 97-kDa mouse macrophage membrane protein that recognizes oxidized low density lipoprotein and phosphatidylserine-rich liposomes is identical to macrosialin, the mouse homologue of human CD68.
    Proc Natl Acad Sci U S A. 1995 Oct 10;92(21):9580-4 PMID: 7568176
  52. Transforming growth factor beta 1 null mutation in mice causes excessive inflammatory response and early death.
    Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):770-4 PMID: 8421714
  53. Corpse clearance defines the meaning of cell death.
    Nature. 2000 Oct 12;407(6805):784-8 PMID: 11048729
  54. Distinct modes of macrophage recognition for apoptotic and necrotic cells are not specified exclusively by phosphatidylserine exposure.
    Mol Biol Cell. 2001 Apr;12(4):919-30 PMID: 11294896
  55. Characterization of phosphatidylserine-dependent beta2-glycoprotein I macrophage interactions. Implications for apoptotic cell clearance by phagocytes.
    J Biol Chem. 1998 Oct 30;273(44):29272-7 PMID: 9786940
  56. Immune clearance of phosphatidylserine-expressing cells by phagocytes. The role of beta2-glycoprotein I in macrophage recognition.
    J Biol Chem. 1997 Dec 5;272(49):31113-7 PMID: 9388264
  57. Human neutrophils lose their surface Fc gamma RIII and acquire Annexin V binding sites during apoptosis in vitro.
    Blood. 1995 Jan 15;85(2):532-40 PMID: 7812008
  58. Independent mechanisms for macrophage binding and macrophage phagocytosis of damaged erythrocytes. Evidence of receptor cooperativity.
    Arterioscler Thromb Vasc Biol. 1997 Dec;17(12):3442-8 PMID: 9437191
  59. Developmental control of endocytosis in dendritic cells by Cdc42.
    Cell. 2000 Aug 4;102(3):325-34 PMID: 10975523
  60. A novel assay for apoptosis. Flow cytometric detection of phosphatidylserine expression on early apoptotic cells using fluorescein labelled Annexin V.
    J Immunol Methods. 1995 Jul 17;184(1):39-51 PMID: 7622868
  61. Loss of phospholipid asymmetry and surface exposure of phosphatidylserine is required for phagocytosis of apoptotic cells by macrophages and fibroblasts.
    J Biol Chem. 2001 Jan 12;276(2):1071-7 PMID: 10986279
  62. Apoptosis. Phagocytic docking without shocking.
    Nature. 1998 Apr 2;392(6675):442-3 PMID: 9548247
  63. ABC1 promotes engulfment of apoptotic cells and transbilayer redistribution of phosphatidylserine.
    Nat Cell Biol. 2000 Jul;2(7):399-406 PMID: 10878804
  64. Thrombospondin cooperates with CD36 and the vitronectin receptor in macrophage recognition of neutrophils undergoing apoptosis.
    J Clin Invest. 1992 Oct;90(4):1513-22 PMID: 1383273
  65. Circular ruffle formation and closure lead to macropinocytosis in hepatocyte growth factor/scatter factor-treated cells.
    Eur J Cell Biol. 1993 Jun;61(1):44-53 PMID: 8223707
  66. Ruffles induced by Salmonella and other stimuli direct macropinocytosis of bacteria.
    Nature. 1993 Aug 12;364(6438):639-42 PMID: 8350922
  67. Membrane traffic during cell locomotion.
    Curr Opin Cell Biol. 1998 Aug;10(4):537-41 PMID: 9719876
  68. Role for the class A macrophage scavenger receptor in the phagocytosis of apoptotic thymocytes in vitro.
    Proc Natl Acad Sci U S A. 1996 Oct 29;93(22):12456-60 PMID: 8901603
  69. The class B scavenger receptors SR-BI and CD36 are receptors for anionic phospholipids.
    J Biol Chem. 1995 Jul 7;270(27):16221-4 PMID: 7541795
  70. Immature dendritic cells phagocytose apoptotic cells via alphavbeta5 and CD36, and cross-present antigens to cytotoxic T lymphocytes.
    J Exp Med. 1998 Oct 5;188(7):1359-68 PMID: 9763615
Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
0021-9525
DOI
10.1083/jcb.200108080
Published
2001-11-12
Epub
2001-00-12
Pages
649-59
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2198875
Subset
IM
Grants
NIGMS NIH HHS · R01 GM061031 · United States
NIGMS NIH HHS · GM60449 · United States
NIGMS NIH HHS · GM61031 · United States
Corrections
CommentIn
PMID: 11706046
External Links
PubMed source DOI: 10.1083/jcb.200108080 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2