Essential role for MFG-E8 as ligand for αvβ5 integrin in diurnal retinal phagocytosis
Essential role for MFG-E8 as ligand for αvβ5 integrin in diurnal retinal phagocytosis
复制标题
DOI：
10.1073/pnas.0704756104
复制
发表时间：
2007-07-17
影响因子：
11.1
通讯作者：
Finnemann, Silvia C.
中科院分区：
文献类型：
--
作者：
Nandrot, Emeline F.;Anand, Monika;Finnemann, Silvia C.
整联蛋白受体Alpha V Beta 5控制视网膜色素上皮（RPE）与相邻光感受器外部段的两种独立形式的相互作用，这对于视觉必不可少。 Alpha v Beta 5专门定位于RPE的顶端微绒毛，并有助于视网膜粘附，该视网膜粘附在始终保持完整的外部段的RPE接触。此外，alpha v beta 5同步了RPE吞噬作用的昼夜爆发，即在昼夜节律中清除光感受器的外部段片段（POS）。视网膜吞噬作用和粘附对Alpha Vβ5受体的依赖性表明，细胞外基质的RPE Microvilli含有该整合素的配体。在这里，我们研究了缺乏功能性MFG-E8表达的小鼠，以测试该整联蛋白配体对视网膜中Alpha V Beta 5功能的贡献。缺乏MFG-E8仅减少了视网膜粘附。相比之下，缺乏MFG-E8（例如缺乏Alpha V Beta 5受体），消除了Alpha V Beta 5的下游信号传导，涉及吞噬受体MERTK和POP POS POS吞噬作用，这两种病都跟随野生型视网膜的轻度发作。原发性培养中的MFG-E8缺陷型RPE保留了正常的上皮形态和顶端alpha vβ5受体的水平，但显示出分离的POS的结合和吞噬受损。可溶性或POS结合的重组MFG-E8足以通过IMFG-E8缺陷型RPE完全恢复吞噬作用。此外，野生型和缺乏MERTK的RPE的MFG-E8补充大大增加了POS的结合，但不影响缺乏Alpha vβ5的RPE的POS结合。因此，MFG-E8刺激节奏性的POS吞噬作用，从RPE的受体。这些结果将MFG-E8识别为视网膜中的第一个细胞外配体，对于昼夜POS吞噬作用至关重要。
The integrin receptor alpha v beta 5 controls two independent forms of interactions of the retinal pigment epithelium (RPE) with adjacent photoreceptor outer segments that are essential for vision. alpha v beta 5 localizes specifically to apical microvilli of the RPE and contributes to retinal adhesion that maintains RPE contacts with intact outer segments at all times. Additionally, alpha v beta 5 synchronizes diurnal bursts of RPE phagocytosis that clear photoreceptor outer segment fragments (POS) shed in a circadian rhythm. Dependence of retinal phagocytosis and adhesion on alpha v beta 5 receptors suggests that the extracellular matrix ensheathing RPE microvilli contains ligands for this integrin. Here we studied mice lacking expression of functional MFG-E8 to test the contribution of this integrin ligand to alpha v beta 5 functions in the retina. Lack of MFG-E8 only minimally reduced retinal adhesion. In contrast, lack of MFG-E8, like lack of alpha v beta 5 receptor, eliminated alpha v beta 5 downstream signaling involving the engulfment receptor MerTK and peak POS phagocytosis, both of which follow light onset in wild-type retina. MFG-E8-deficient RPE in primary culture retained normal epithelial morphology and levels of apical alpha v beta 5 receptors, but showed impaired binding and engulfment of isolated POS. Soluble or POS-bound recombinant MFG-E8 was sufficient to fully restore phagocytosis by IMFG-E8-deficient RPE. Furthermore, MFG-E8 supplementation strongly increased POS binding by wild-type and MerTK-deficient RPE, but did not affect POS binding by RPE lacking alpha v beta 5. Thus, MFG-E8 stimulates rhythmic POS phagocytosis by ligating apical alpha v beta 5 receptors of the RPE. These results identify MFG-E8 as the first extracellular ligand in the retina that is essential for diurnal POS phagocytosis.