Galectin-3/MAC-2, Ras and PI3K Activate Complement Receptor-3 and Scavenger Receptor-AI/II Mediated Myelin Phagocytosis in Microglia
Galectin-3/MAC-2, Ras and PI3K Activate Complement Receptor-3 and Scavenger Receptor-AI/II Mediated Myelin Phagocytosis in Microglia
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DOI：
10.1002/glia.20713
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发表时间：
2008-11-15
期刊：
影响因子：
6.2
通讯作者：
Kloog, Yoel
中科院分区：
文献类型：
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作者：
Rotshenker, Shlomo;Reichert, Fanny;Kloog, Yoel
变性髓鞘的去除对于轴突创伤性损伤后的沃勒变性和自身免疫性脱髓鞘疾病（例如，多发性硬化症）。小胶质细胞可以通过补体受体3（CR 3/MAC-1）和清道夫受体AI/II（SRAI/II）介导的磷脂酰肌醇-3-激酶（PI 3 K）依赖性吞噬作用清除变性的髓鞘。特别地，这些受体在损伤后在小胶质细胞中表达，但髓鞘不被吞噬。此外，半乳糖凝集素-3/MAC-2在吞噬的小胶质细胞中表达，但在不吞噬的小胶质细胞中不表达，表明半乳糖凝集素-3/MAC-2有助于激活吞噬作用。S-反式，反式法尼基硫代水杨酸（FTS），抑制半乳糖凝集素-3/MAC-2依赖性激活PI 3 K通过Ras，抑制吞噬作用。K-Ras-GTP水平和PI 3 K活性在正常吞噬过程中增加，在FTS抑制的吞噬过程中降低。半乳糖凝集素-3/MAC-2，其结合并稳定活性Ras，与Ras共免疫沉淀，并且在正常吞噬作用期间共免疫沉淀物的水平增加。因此，提示了半乳糖凝集素-3/MAC-2依赖性通过Ras（主要是K-Ras）激活PI 3 K的作用。因此，可以解释表达CR 3/MAC-1和SRAI/II而没有半乳糖凝集素-3/MAC-2的小胶质细胞的吞噬作用不足，以及当CR 3/MAC-1和SRAI/II与半乳糖凝集素-3/MAC-2共表达时的有效吞噬作用。(C)2008 Wiley-Liss，Inc.
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. (C) 2008 Wiley-Liss,Inc.