In Glaucoma the Upregulated Truncated TrkC.T1 Receptor Isoform in Glia Causes Increased TNF-α Production, Leading to Retinal Ganglion Cell Death
In Glaucoma the Upregulated Truncated TrkC.T1 Receptor Isoform in Glia Causes Increased TNF-α Production, Leading to Retinal Ganglion Cell Death
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DOI：
10.1167/iovs.10-5431
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发表时间：
2010-12-01
影响因子：
4.4
通讯作者：
Saragovi, H. Uri
中科院分区：
文献类型：
--
作者：
Bai, Yujing;Shi, ZhiHua;Saragovi, H. Uri
目的。青光眼是一种独特的神经病变，其特征是视网膜神经节细胞（RGCs）的慢性和进行性死亡。RGC死亡的病因尚不清楚。青光眼RGC死亡的危险因素是眼压升高和肿瘤坏死因子- α (tnf - α)的胶质生成。先前，作者表明青光眼导致缺乏激酶结构域TrkC的神经营养因子受体截断异构体的快速上调。T1在视网膜上。在这里，他们研究了TrkC的生物学作用。T1在青光眼进展期间。采用大鼠和小鼠慢性高眼压模型。免疫荧光Western blot和原位mRNA杂交检测TrkC.T1表达上调的细胞。缺乏TrkC的工程小鼠遗传模型。T1（TrkC.T1(-/-)）被用来验证该受体在青光眼中的作用。进行药理学研究以评估TrkC激动剂或拮抗剂的玻璃体内递送。T1，与对照组相比，青光眼期间。通过逆行标记技术对存活的RGCs进行量化。定量测定神经毒性tnf - α和α 2巨球蛋白的产生。TrkC。T1在视网膜胶质细胞中上调，其模式与tnf - α相似。TrkC。T1（-/-）小鼠视网膜正常。然而，在实验性青光眼中，TrkC。与野生型小鼠相比，T1（/）小鼠的RGC死亡率较低，产生的tnf - α较少。在青光眼大鼠中，使用TrkC拮抗剂可延缓RGC死亡并减少视网膜tnf - α的产生。TrkC。T1通过控制胶质细胞tnf - α的产生与青光眼RGC死亡有关。总的来说，这些数据指出了一种旁分泌机制，即眼压升高上调胶质细胞TrkC。T1在胶质细胞中的表达；TrkC。T1控制胶质细胞tnf - α的产生，tnf - α引起RGC死亡。（中国眼科杂志，2010;51:6639-6651）DOI:10.1167/iovs.10-5431
PURPOSE. Glaucoma is a distinct neuropathy characterized by the chronic and progressive death of retinal ganglion cells (RGCs). The etiology of RGC death remains unknown. Risk factors for glaucomatous RGC death are elevated intraocular pressure and glial production of tumor necrosis factor-alpha (TNF-alpha). Previously, the authors showed that glaucoma causes a rapid upregulation of a neurotrophin receptor truncated isoform lacking the kinase domain, TrkC.T1, in retina. Here they examined the biological role of TrkC.T1 during glaucoma progression.METHODS. Rat and mouse models of chronic ocular hypertension were used. Immunofluorescence Western blot analysis and in situ mRNA hybridization were used to identify cells upregulating TrkC.T1. A genetic model of engineered mice lacking TrkC.T1 (TrkC.T1(-/-)) was used to validate a role for this receptor in glaucoma. Pharmacologic studies were conducted to evaluate intravitreal delivery of agonists or antagonists of TrkC. T1, compared with controls, during glaucoma. Surviving RGCs were quantified by retrograde-labeling techniques. Production of neurotoxic TNF-alpha and alpha 2 macroglobulin were quantified.RESULTS. TrkC.T1 was upregulated in retinal glia, with a pattern similar to that of TNF-alpha. TrkC.T1(-/-) mice had normal retinas. However, during experimental glaucoma, TrkC.T1 (/) mice had lower rates of RGC death and produced less TNF-alpha than wild-type littermates. In rats with glaucoma, the pharmacologic use of TrkC antagonists delayed RGC death and reduced the production of retinal TNF-alpha.CONCLUSIONS. TrkC.T1 is implicated in glaucomatous RGC death through the control of glial TNF-alpha production. Overall, the data point to a paracrine mechanism whereby elevated intraocular pressure upregulated glial TrkC.T1 expression in glia; TrkC.T1 controlled glial TNF-alpha production, and TNF-alpha caused RGC death. (Invest Ophthalmol Vis Sci. 2010; 51: 6639-6651) DOI:10.1167/iovs.10-5431