Complement receptor-3 negatively regulates the phagocytosis of degenerated myelin through tyrosine kinase Syk and cofilin.
Complement receptor-3 negatively regulates the phagocytosis of degenerated myelin through tyrosine kinase Syk and cofilin.
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DOI：
10.1186/1742-2094-9-166
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发表时间：
2012-07-09
影响因子：
9.3
通讯作者：
Rotshenker S
中科院分区：
文献类型：
--
作者：
Hadas S;Spira M;Hanisch UK;Reichert F;Rotshenker S
正常情况下围绕轴突的完整髓鞘在轴突损伤后的沃勒变性中分解，在多发性硬化症等神经退行性疾病中分解。通过吞噬清除退化的髓鞘是必不可少的，因为髓鞘阻碍修复并加剧损伤。补体受体-3(CR3)是髓鞘吞噬过程中的主要吞噬受体。我们研究了酪氨酸激酶Syk(脾酪氨酸激酶)和Cofilin如何控制CR3吞噬小胶质细胞和巨噬细胞中退化的髓鞘。SYK是一种非受体酪氨酸激酶，CR3招募它来传递细胞功能。Cofilin是一种肌动蛋白解聚蛋白，通过在活性的非磷酸化和非活性的磷酸化状态之间转换来控制F-肌动蛋白(丝状肌动蛋白)的重塑(即分解和重组)。在长时间吞噬过程中，SYK被持续激活。当Syk活性和表达降低时，吞噬作用增加，这表明Syk正常情况下下调了CR3介导的髓鞘吞噬。在长时间的吞噬过程中，非活性的p-cofilin(磷酸化cofilin)的水平会短暂下降。相反，当Syk活性和表达持续降低时，p-cofilin水平持续下降，这表明正常情况下Syk促进了cofilin的非活动状态。观察还发现吞噬水平和非活性p-cofilin水平之间呈负相关，这表明活性的非磷酸化cofilin促进了吞噬作用。活性粘附素可以通过促进F-肌动蛋白重塑来促进吞噬作用，F-肌动蛋白重塑支持膜突起的产生(例如，丝状足突)，正如我们还揭示的，这在髓鞘吞噬中起着重要作用。CR3同时激活和下调髓鞘吞噬功能。激活之前已记录在案。我们目前证明，下调是通过Syk介导的，Syk促进了cofilin的非活性磷酸化状态。吞噬细胞受体对吞噬作用的自我负性控制有助于保护吞噬细胞在长期暴露于注定要摄入的颗粒时避免过度吞噬(即“过量进食”)。
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.
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影响因子：
6.2
作者：
Rotshenker, Shlomo;Reichert, Fanny;Kloog, Yoel
通讯作者：
Kloog, Yoel
影响因子：
3.1
作者：
Rotshenker, S
通讯作者：
Rotshenker, S
影响因子：
6.2
作者：
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影响因子：
20.3
作者：
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影响因子：
2.7
作者：
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