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Galectin-3/MAC-2, Ras and PI3K activate complement receptor-3 and scavenger receptor-AI/II mediated myelin

Shlomo Rotshenker1, Fanny Reichert, Miri Gitik

  • 1Department of Anatomy and Cell Biology, Hebrew University Faculty of Medicine, and the Eric Roland Center for Neurodegenerative Diseases, Jerusalem, Israel. shlomor@ekmd.huji.ac.il

Glia
|July 11, 2008
PubMed

Insights

Microglia phagocytosis of myelin is crucial for nerve repair. Galectin-3/MAC-2 activates this process via PI3K and Ras signaling, explaining why some microglia fail to clear myelin debris.

Area of Science:

  • Neuroscience
  • Immunology
  • Cell Biology

Background:

  • Myelin removal is vital for nerve repair after injury and in diseases like multiple sclerosis.
  • Microglia, immune cells in the brain, are responsible for clearing myelin debris.
  • Receptors like CR3/MAC-1 and SRAI/II are involved in myelin phagocytosis, but their function can be impaired.

Purpose of the Study:

  • To investigate the mechanism behind impaired myelin phagocytosis by microglia.
  • To identify the role of Galectin-3/MAC-2 in activating microglial phagocytosis.
  • To elucidate the signaling pathway involving PI3K and Ras in this process.

Main Methods:

  • Utilized in vitro models of Wallerian degeneration and demyelinating diseases.
  • Assessed microglial phagocytosis of myelin.
  • Analyzed the expression and activity of Galectin-3/MAC-2, CR3/MAC-1, SRAI/II, Ras, and PI3K.
  • Used S-trans, trans-farnesylthiosalicylic (FTS) to inhibit Galectin-3/MAC-2/Ras/PI3K signaling.

Main Results:

  • Microglia expressing CR3/MAC-1 and SRAI/II but lacking Galectin-3/MAC-2 showed deficient myelin phagocytosis.
  • Galectin-3/MAC-2 expression correlated with efficient phagocytosis.
  • Inhibition of Galectin-3/MAC-2/Ras/PI3K pathway by FTS reduced phagocytosis.
  • K-Ras-GTP levels and PI3K activity increased during phagocytosis and decreased upon FTS treatment.
  • Galectin-3/MAC-2 was found to bind and stabilize active Ras, coimmunoprecipitating with it.

Conclusions:

  • Galectin-3/MAC-2 is essential for activating microglial myelin phagocytosis.
  • The mechanism involves Galectin-3/MAC-2-dependent activation of PI3K signaling through Ras, primarily K-Ras.
  • This finding explains why microglia may fail to clear myelin debris in certain conditions, offering therapeutic targets for demyelinating diseases.

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