Department of Ophthalmology, Eye, Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China.
Laboratory of Myopia, NHC Key Laboratory of Myopia (Fudan University), Chinese Academy of Medical Sciences, Shanghai, China.
J Cell Mol Med. 2019 Nov;23(11):7602-7616. doi: 10.1111/jcmm.14633. Epub 2019 Aug 28.
Corneal lymphangiogenesis plays a key role in diverse pathological conditions of the eye. Here, we demonstrate that a versatile extracellular matrix protein, transforming growth factor-β induced protein (TGFBIp), promotes lymphatic sprouting in corneal lymphangiogenesis. TGFBIp is highly up-regulated in inflamed mouse corneas. Immunolocalization of TGFBIp is detected in infiltrating macrophages in inflamed mouse corneas. Subconjunctival injection of liposomal clodronate can significantly reduce macrophage infiltration in inflamed mouse cornea, and decrease the expression of TGFBIp and areas of corneal lymphangiogenesis and angiogenesis after corneal suture placement. In brief, these results indicate that the up-regulation of TGFBIp in sutured cornea correlates with macrophage infiltration. Although TGFBIp alone cannot significantly stimulate corneal lymph vessel ingrowth in vivo, it can enhance the effect of vascular endothelial growth factor-C in promoting corneal lymphangiogenesis. The in vitro results show that TGFBIp promotes migration, tube formation and adhesion of human lymphatic endothelial cells (HLECs), but it has no effect on HLECs' proliferation. We also find that the in vitro effect of TGFBIp is mediated by the integrin α5β1-FAK pathway. Additionally, integrin α5β1 blockade can significantly inhibit lymphatic sprouting induced by TGFBIp. Taken together, these findings reveal a new molecular mechanism of lymphangiogenesis in which the TGFBIp-integrin pathways plays a pivotal role in lymphatic sprouting.
角膜淋巴管生成在眼部多种病理状态中起着关键作用。在这里，我们证明了一种多功能细胞外基质蛋白，转化生长因子-β诱导蛋白（TGFBIp），可促进角膜淋巴管生成中的淋巴管发芽。TGFBIp 在发炎的小鼠角膜中高度上调。在发炎的小鼠角膜中浸润的巨噬细胞中检测到 TGFBIp 的免疫定位。结膜下注射脂质体氯膦酸盐可显著减少炎症性小鼠角膜中的巨噬细胞浸润，并减少角膜缝线放置后 TGFBIp 的表达以及角膜淋巴管生成和血管生成的面积。总之，这些结果表明，缝合角膜中 TGFBIp 的上调与巨噬细胞浸润有关。虽然 TGFBIp 单独不能显著刺激体内角膜淋巴管的生长，但它可以增强血管内皮生长因子-C 促进角膜淋巴管生成的作用。体外结果表明，TGFBIp 促进人淋巴管内皮细胞（HLEC）的迁移、管形成和黏附，但对 HLEC 的增殖没有影响。我们还发现，TGFBIp 的体外作用是通过整合素 α5β1-FAK 途径介导的。此外，整合素 α5β1 阻断可显著抑制 TGFBIp 诱导的淋巴管发芽。总之，这些发现揭示了淋巴管生成的新分子机制，其中 TGFBIp-整合素途径在淋巴管发芽中起着关键作用。
