Dept. of Medical Neurobiology, IMRIC, Hebrew University Faculty of Medicine, Ein-Kerem, 12272, Jerusalem 91120, Israel.
J Neuroinflammation. 2012 Jul 9;9:166. doi: 10.1186/1742-2094-9-166.
Intact myelin, which normally surrounds axons, breaks down in Wallerian degeneration following axonal injury and during neurodegenerative diseases such as multiple sclerosis. Clearance of degenerated myelin by phagocytosis is essential since myelin impedes repair and exacerbates damage. CR3 (complement receptor-3) is a principal phagocytic receptor in myelin phagocytosis. We studied how tyrosine kinase Syk (spleen tyrosine kinase) and cofilin control phagocytosis of degenerated myelin by CR3 in microglia and macrophages. Syk is a non-receptor tyrosine kinase that CR3 recruits to convey cellular functions. Cofilin is an actin-depolymerizing protein that controls F-actin (filamentous actin) remodeling (i.e., disassembly and reassembly) by shifting between active unphosphorylated and inactive phosphorylated states.
Syk was continuously activated during prolonged phagocytosis. Phagocytosis increased when Syk activity and expression were reduced, suggesting that normally Syk down regulates CR3-mediated myelin phagocytosis. Levels of inactive p-cofilin (phosphorylated cofilin) decreased transiently during prolonged phagocytosis. In contrast, p-cofilin levels decreased continuously when Syk activity and expression were continuously reduced, suggesting that normally Syk advances the inactive state of cofilin. Observations also revealed inverse relationships between levels of phagocytosis and levels of inactive p-cofilin, suggesting that active unphosphorylated cofilin advances phagocytosis. Active cofilin could advance phagocytosis by promoting F-actin remodeling, which supports the production of membrane protrusions (e.g., filopodia), which, as we also revealed, are instrumental in myelin phagocytosis.
CR3 both activates and downregulates myelin phagocytosis at the same time. Activation was previously documented. We presently demonstrate that downregulation is mediated through Syk, which advances the inactive phosphorylated state of cofilin. Self-negative control of phagocytosis by the phagocytic receptor can be useful in protecting phagocytes from excessive phagocytosis (i.e., "overeating") during extended exposure to particles that are destined for ingestion.
在轴突损伤后以及在多发性硬化等神经退行性疾病中，正常围绕轴突的完整髓磷脂会在瓦勒氏变性中分解。吞噬作用清除变性的髓磷脂是必不可少的，因为髓磷脂会阻碍修复并加剧损伤。CR3（补体受体 3）是髓磷脂吞噬作用中的主要吞噬受体。我们研究了脾酪氨酸激酶 Syk（Spleen Tyrosine Kinase）和丝切蛋白如何控制 CR3 吞噬小胶质细胞和巨噬细胞中的变性髓磷脂。Syk 是一种非受体酪氨酸激酶，CR3 通过它来传递细胞功能。丝切蛋白是一种肌动蛋白解聚蛋白，通过在活性非磷酸化和非活性磷酸化状态之间转换来控制 F-肌动蛋白（丝状肌动蛋白）重塑（即解聚和重组）。
在长时间的吞噬作用中，Syk 持续激活。当 Syk 活性和表达降低时，吞噬作用增加，这表明正常情况下 Syk 下调 CR3 介导的髓磷脂吞噬作用。在长时间的吞噬作用中，无活性的 p-丝切蛋白（磷酸化丝切蛋白）水平短暂下降。相比之下，当 Syk 活性和表达持续降低时，p-丝切蛋白水平持续下降，这表明正常情况下 Syk 促进丝切蛋白的非活性状态。观察结果还揭示了吞噬作用水平和无活性 p-丝切蛋白水平之间的反比关系，这表明活性非磷酸化丝切蛋白促进吞噬作用。活性丝切蛋白可以通过促进 F-肌动蛋白重塑来促进吞噬作用，这支持了膜突起（例如，丝状伪足）的产生，正如我们也揭示的那样，这些突起在髓磷脂吞噬作用中是必不可少的。
CR3 同时激活和下调髓磷脂吞噬作用。激活作用以前已有报道。我们现在证明，下调作用是通过 Syk 介导的，它促进了丝切蛋白的非活性磷酸化状态。吞噬受体的自我负性控制可用于在延长暴露于注定要摄入的颗粒时防止吞噬细胞过度吞噬（即“过度进食”）。
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