Tubby regulates microglial phagocytosis through MerTK.
Tubby regulates microglial phagocytosis through MerTK.
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DOI：
10.1016/j.jneuroim.2012.07.009
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发表时间：
2012-11-15
影响因子：
3.3
通讯作者：
Li, Wei
中科院分区：
文献类型：
--
作者：
Caberoy, Nora B.;Alvarado, Gabriela;Li, Wei
凋亡细胞和细胞碎片的免疫沉默的小胶质细胞吞噬作用对于CNS稳态和先天免疫平衡至关重要。小胶质细胞吞噬作用对神经元的有益和有害影响仍然存在争议。吞噬作用配体是选择细胞外物质、启动吞噬过程、确定吞噬细胞功能作用和调节具有治疗潜力的吞噬细胞活性的关键。在这里，我们将tubby作为一种新的配体，通过MerTK受体来调节小胶质细胞的吞噬作用，MerTK受体以其免疫抑制信号而闻名。0.1 nM的Tubby显著诱导凋亡细胞的小胶质细胞吞噬作用，最大活性为10 nM。Tubby在相似的剂量范围内通过受体自磷酸化激活MerTK。过量的可溶性MerTK胞外结构域阻断了tubby介导的小胶质细胞对质膜囊泡作为细胞碎片的吞噬作用。免疫细胞化学显示，摄取的货物共定位与MerTK依赖性非肌肉肌球蛋白II，其重排是必要的货物吞噬。吞噬体生物标志物Rab 7与货物共定位，表明内化的货物靶向吞噬途径。Tubby刺激吞噬新生儿和老年小胶质细胞具有相似的活动，但不是由MerTK−/−小胶质细胞。这些结果表明，tubby是一种配体，通过MerTK促进小胶质细胞的吞噬作用，以维持CNS稳态。
Immunologically-silent microglial phagocytosis of apoptotic cells and cellular debris is critical for CNS homeostasis and innate immune balance. The beneficial and detrimental effects of microglial phagocytosis on neurons remain controversial. Phagocytosis ligands are the key to selecting extracellular cargos, initiating the engulfment process, defining phagocyte functional roles and regulating phagocyte activities with therapeutic potentials. Here we characterized tubby as a new ligand to regulate microglial phagocytosis through MerTK receptor, which is well known for its immunosuppressive signaling. Tubby at 0.1 nM significantly induced microglial phagocytosis of apoptotic cells with a maximal activity at 10 nM. Tubby activated MerTK with receptor autophosphorylation in a similar dose range. Excessive soluble MerTK extracellular domain blocked tubby-mediated microglial phagocytosis of plasma membrane vesicles as cellular debris. Immunocytochemistry revealed that the ingested cargos were co-localized with MerTK-dependent non-muscle myosin II, whose rearrangement is necessary for cargo engulfment. Phagosome biomarker Rab7 was colocalized with cargos, suggesting that internalized cargos were targeted to phagocytic pathway. Tubby stimulated phagocytosis by neonatal and aged microglia with similar activities, but not by MerTK−/− microglia. These results suggest that tubby is a ligand to facilitate microglial phagocytosis through MerTK for the maintenance of CNS homeostasis.
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影响因子：
4.2
作者：
Njie EG;Boelen E;Stassen FR;Steinbusch HW;Borchelt DR;Streit WJ
通讯作者：
Streit WJ
影响因子：
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作者：
Caberoy NB;Zhou Y;Li W
通讯作者：
Li W
影响因子：
30.8
作者：
Gal, A;Li, Y;Vollrath, D
通讯作者：
Vollrath, D
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作者：
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通讯作者：
Brown, Guy C.
影响因子：
6.2
作者：
Grommes, Christian;Lee, C. Y. Daniel;Landreth, Gary E.
通讯作者：
Landreth, Gary E.