MFG-E8 regulates microglial phagocytosis of apoptotic neurons

Abby D. Fuller, Linda J. Van Eldik

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

Abstract

Phagocytosis is an essential mechanism for clearance of pathogens, dying cells, and other unwanted debris in order to maintain tissue health in the body. Macrophages execute this process in the peripheral immune system but in the brain microglia act as resident macrophages to accomplish this function. In the peripheral immune system, macrophages secrete Milk Fat Globule Factor-E8 (MFG-E8) that recognizes phosphatidylserine "eat me" signals expressed on the surface of apoptotic cells. MFG-E8 then acts as a tether to attach the apoptotic cell to the macrophage and trigger a signaling cascade that stimulates the phagocyte development, allowing the macrophage to engulf the dying cell. When this process becomes disrupted, inflammation and autoimmunity can result. MFG-E8 resides in the brain as well as in the periphery, and microglia express MFG-E8. However, the function of MFG-E8 in the brain has not been elucidated. We measured MFG-E8 production in the BV-2 microglial cell line and the role of this protein in the recognition and engulfment of apoptotic SY5Y neuroblastoma cells. BV-2 cells produced and released MFG-E8, which apoptotic SY5Y cells and the chemokine fractalkine further stimulated. Furthermore, MFG-E8 increased phagocytosis of apoptotic SY5Y cells, and a dominant negative form of MFG-E8 inhibited phagocytosis by BV-2 cells. Finally, brain MFG-E8 levels were altered in a mouse model of Alzheimer's disease. Our data suggest that MFG-E8 acts in the brain via microglia to aid in clearance of apoptotic neurons, and we hypothesize that a dysregulation of this process may be involved in neurodegenerative disease.

Original languageEnglish
Pages (from-to)246-256
Number of pages11
JournalJournal of NeuroImmune Pharmacology
Volume3
Issue number4
DOIs
StatePublished - Dec 2008

Bibliographical note

Funding Information:
Sources of support This work was supported in part by NIH grant R37 AG013939. AF was a predoctoral trainee on NIH T32 AG000260 and is currently supported by NIH F31 NS052043 predoctoral fellowship.

Keywords

  • Alzheimer's disease
  • Apoptosis
  • Fractalkine
  • MFG-E8
  • Microglia
  • Phagocytosis

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

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