Galectin-3/MAC-2, Ras and PI3K activate complement receptor-3 and scavenger receptor-AI/II mediated myelin phagocytosis in microglia.
The removal of degenerated myelin is essential for repair in Wallerian degeneration that follows traumatic injury to axons and in autoimmune demyelinating diseases (e.g., multiple sclerosis). Microglia can remove degenerated myelin through phosphatidylinositol-3-kinase (PI3K)-dependent phagocytosis mediated by complement receptor-3 (CR3/MAC-1) and scavenger receptor-AI/II (SRAI/II). Paradoxically, these receptors are expressed in microglia after injury but myelin is not phagocytosed. Additionally, Galectin-3/MAC-2 is expressed in microglia that phagocytose but not in microglia that do not phagocytose, suggesting that Galectin-3/MAC-2 is instrumental in activating phagocytosis. S-trans, trans-farnesylthiosalicylic (FTS), which inhibits Galectin-3/MAC-2 dependent activation of PI3K through Ras, inhibited phagocytosis. K-Ras-GTP levels and PI3K activity increased during normal phagocytosis and decreased during FTS-inhibited phagocytosis. Galectin-3/MAC-2, which binds and stabilizes active Ras, coimmunoprecipitated with Ras and levels of the coimmunoprecipitate increased during normal phagocytosis. A role for Galectin-3/MAC-2 dependent activation of PI3K through Ras, mostly K-Ras, is thus suggested. An explanation may thus be offered for deficient phagocytosis by microglia that express CR3/MAC-1 and SRAI/II without Galectin-3/MAC-2 and efficient phagocytosis when CR3/MAC-1 and SRAI/II are co-expressed with Galectin-3/MAC-2.
Rotshenker
Shlomo
S
Department 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
Reichert
Fanny
F
Gitik
Miri
M
Haklai
Ronit
R
Elad-Sfadia
Galit
G
Kloog
Yoel
Y
D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D037502:Galectin 3 / Q000378:metabolism*; D005911:Gliosis / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D016177:Macrophage-1 Antigen / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000276:immunology*; D009186:Myelin Sheath / Q000378:metabolism*; D009416:Nerve Regeneration / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D014855:Wallerian Degeneration / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D018631:ras Proteins / Q000378:metabolism
D037502:Galectin 3; D016177:Macrophage-1 Antigen; D051117:Scavenger Receptors, Class A; D019869:Phosphatidylinositol 3-Kinases; D018631:ras Proteins