Skip to main content
Article thumbnail
Location of Repository

Masking of Phosphatidylserine Inhibits Apoptotic Cell Engulfment and Induces Autoantibody Production in Mice

By Kenichi Asano, Miyu Miwa, Keiko Miwa, Rikinari Hanayama, Hiroko Nagase, Shigekazu Nagata and Masato Tanaka

Abstract

Apoptotic cells are rapidly phagocytosed by professional phagocytes, such as macrophages and dendritic cells. This process prevents the release of potentially noxious or immunogenic intracellular materials from dying cells, and is thought to play a critical role for the maintenance of normal functions in surrounding tissues. Milk fat globule-EGF-factor 8 (MFG-E8), secreted by activated macrophages and immature dendritic cells, links apoptotic cells and phagocytes, and promotes phagocytosis of apoptotic cells. Here, we report that an MFG-E8 mutant, designated as D89E, carrying a point mutation in an RGD motif, inhibited not only the phagocytosis of apoptotic cells by a wide variety of phagocytes, but also inhibited the enhanced production of IL-10 by thioglycollate-elicited peritoneal macrophages phagocytosing apoptotic cells. When intravenously injected into mice, the D89E protein induced the production of autoantibodies including antiphospholipids antibodies and antinuclear antibodies. The production of autoantibodies was enhanced by the coinjection of syngeneic apoptotic thymocytes. After the induction of autoantibody production by D89E, the treated mice showed a long-term elevation of the titer for autoantibodies, and developed IgG deposition in the glomeruli. These results indicated that the impairment of apoptotic cell phagocytosis led to autoantibody production

Topics: Article
Publisher: The Rockefeller University Press
OAI identifier: oai:pubmedcentral.nih.gov:2211927
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles

    Citations

    1. (2002). A blast from the past: clearance of apoptotic cells regulates immune responses.
    2. (2000). A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo.
    3. (2000). A receptor for phosphatidylserine-specific clearance of apoptotic cells.
    4. (2000). An auxiliary mode of apoptotic DNA fragmentation provided by phagocytes. Genes Dev.
    5. (1997). Apoptosis by death factor.
    6. (2001). Apoptosis: corralling the corpses.
    7. (1998). Apoptosis: the importance of being eaten. Cell Death Differ.
    8. (2004). Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice.
    9. (1990). cDNA cloning of a mouse mammary epithelial cell surface protein reveals the existence of epidermal growth factor-like domains linked to factor VIIIlike sequences.
    10. (1999). Cell death in devel-Inhibition of Apoptotic Cell Clearance Causes Autoimmunity 466 opment.
    11. (2000). Corpse clearance defines the meaning of cell death.
    12. (1998). Death by a thousand cuts: an ever increasing list of caspase substrates. Cell Death Differ.
    13. (2002). Delayed apoptotic cell clearance and lupuslike autoimmunity in mice lacking the c-mer membrane tyrosine kinase.
    14. (2004). Expression of Del-1 in a subset of macrophages for engulfment of apoptotic cells.
    15. (1998). Homozygous C1q deficiency causes glomerulonephritis associated with multiple apoptotic bodies.
    16. (2003). Hsp70 promotes antigenpresenting cell function and converts T-cell tolerance to au-Asano et al. 467 toimmunity in vivo.
    17. (2002). Identification of a factor that links apoptotic cells to phagocytes.
    18. (2002). Immune tolerance after delivery of dying cells to dendritic cells in situ.
    19. (1994). Immunologically cross-reactive 57 kDa and 53 kDa glycoprotein antigens of bovine milk fat globule membrane: isoforms with different N-linked sugar chains and differential glycosylation at early stages of lactation.
    20. (1997). Immunosuppressive effects of apoptotic cells.
    21. Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation.
    22. (1998). Induction of anti-phospholipid autoantibodies by beta2-glycoprotein I bound to apoptotic thymocytes.
    23. Induction of antiphospholipid autoantibodies by immunization with beta 2
    24. (2003). Lactadherin inhibits enzyme complexes of blood coagulation by competing for phospholipid-binding sites.
    25. (1999). Lactation-dependent expression of an mRNA splice variant with an exon for a multiply O-glycosylated domain of mouse milk fat globule glycoprotein MFGE8.
    26. (1998). Lectin-like oxidized low-density lipoprotein receptor 1 mediates phagocytosis of aged/apoptotic cells in endothelial cells.
    27. (2002). Lipopolysaccharide induces rapid production of IL-10 by monocytes in the presence of apoptotic neutrophils.
    28. (1999). Mechanisms of phagocytosis in macrophages.
    29. (1995). Molecular cloning of glycoprotein antigens MGP57/53 recognized by monoclonal antibodies raised against bovine milk fat globule membrane.
    30. (2003). Molecular identification of a danger signal that alerts the immune system to dying cells.
    31. (2001). Phagocytosis and clearance of apoptotic cells is mediated by MER.
    32. (2001). Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells.
    33. (2002). Phosphatidylserine binding of class B scavenger receptor type I, a phagocytosis receptor of testicular sertoli cells.
    34. (1997). Programmed cell death in animal development.
    35. (1998). Recognizing death: the phagocytosis of apoptotic cells. Trends Cell Biol.
    36. (2003). Serum-derived protein S binds to phosphatidylserine and stimulates the phagocytosis of apoptotic cells.
    37. (1997). Stage specific expression of milk fat globule membrane glycoproteins in mouse mammary gland: comparison of MFG-E8, butyrophilin, and CD36 with a major milk protein, beta-casein.
    38. (1998). Systemic exposure to irradiated apoptotic cells induces autoantibody production.
    39. (2003). Tethering of apoptotic cells to phagocytes through binding of CD47 to Src homology 2 domain-bearing protein tyrosine phosphatase substrate-1.
    40. (1998). The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. Cell Death Differ.

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.