Deletion of Tgfβ signal in activated microglia prolongs hypoxia-induced retinal neovascularization enhancing Igf1 expression and retinal leukostasis.
Deletion of Tgfβ signal in activated microglia prolongs hypoxia-induced retinal neovascularization enhancing Igf1 expression and retinal leukostasis.
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DOI：
10.1002/glia.24218
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发表时间：
2022-09
期刊：
影响因子：
6.2
通讯作者：
Friedlander, Martin
中科院分区：
文献类型：
--
作者：
Usui-Ouchi, Ayumi;Eade, Kevin;Giles, Sarah;Ideguchi, Yoichiro;Ouchi, Yasuo;Aguilar, Edith;Wei, Guoqin;Marra, Kyle V.;Berlow, Rebecca B.;Friedlander, Martin
关键词：
视网膜新生血管是导致缺血性眼病患者严重视力损害的主要原因。虽然已知视网膜小胶质细胞参与生理性和病理性血管生成，但这些胶质细胞调节病理性新生血管形成的分子机制尚未完全阐明。在这项研究中，我们利用视网膜小胶质细胞特异性转化生长因子-β(转化生长因子-β)受体敲除的小鼠模型和人IPSC来源的小胶质细胞来检测转化生长因子β信号在视网膜新生血管病变过程中激活的小胶质细胞中的作用。利用他莫昔芬诱导的、小胶质细胞特异性的转化生长因子β受体2型(转化生长因子βR2)基因敲除小鼠[转化生长因子βR2 KO(ΔMG)]，我们发现小胶质细胞中的转化生长因子β信号积极抑制视网膜血管中的白血球沉积。此外，我们发现转化生长因子β信号抑制促血管生成因子胰岛素样生长因子1的表达，而不依赖于血管内皮生长因子的调节。利用小鼠氧诱导视网膜病变模型，我们证明了转化生长因子β信号在低氧诱导的视网膜新生血管中起一定作用，其中转化生长因子β信号的缺失加剧和延长了视网膜新生血管。利用体外培养的人IPSC来源的小胶质细胞，我们验证了转化生长因子-β1(TGF1)在低氧条件下调节β1表达的作用。最后，我们发现小胶质细胞中的转化生长因子β信号对小胶质细胞的动态平衡是必不可少的，小胶质细胞中转化生长因子β信号的中断通过促进白细胞停滞和免疫球蛋白1的表达而加重了OIR的视网膜新生血管。阻断视网膜小胶质细胞转化生长因子β信号诱导活化并通过促进白细胞抑制和免疫球蛋白1上调而加重新生血管形成转化生长因子β1调节小胶质细胞免疫球蛋白1的表达，挽救低氧诱导的小胶质细胞免疫球蛋白1上调
Retinal neovascularization (NV) is the major cause of severe visual impairment in patients with ischemic eye diseases. While it is known that retinal microglia contribute to both physiological and pathological angiogenesis, the molecular mechanisms by which these glia regulate pathological NV have not been fully elucidated. In this study, we utilized a retinal microglia‐specific Transforming Growth Factor‐β (Tgfβ) receptor knock out mouse model and human iPSC‐derived microglia to examine the role of Tgfβ signaling in activated microglia during retinal NV. Using a tamoxifen‐inducible, microglia‐specific Tgfβ receptor type 2 (Tgfβr2) knockout mouse [Tgfβr2 KO (ΔMG)] we show that Tgfβ signaling in microglia actively represses leukostasis in retinal vessels. Furthermore, we show that Tgfβ signaling represses expression of the pro‐angiogenic factor, Insulin‐like growth factor 1 (Igf1), independent of Vegf regulation. Using the mouse model of oxygen‐induced retinopathy (OIR) we show that Tgfβ signaling in activated microglia plays a role in hypoxia‐induced NV where a loss in Tgfβ signaling microglia exacerbates and prolongs retinal NV in OIR. Using human iPSC‐derived microglia cells in an in vitro assay, we validate the role of Transforming Growth Factor‐β1 (Tgfβ1) in regulating Igf1 expression in hypoxic conditions. Finally, we show that Tgfβ signaling in microglia is essential for microglial homeostasis and that the disruption of Tgfβ signaling in microglia exacerbates retinal NV in OIR by promoting leukostasis and Igf1 expression. Blocking Tgfβ signaling in retinal microglia induces activation and worsens OIR neovascularization by promoting leukostasis and Igf1 upregulation Tgfβ1 regulates Igf1 expression in microglia, rescuing hypoxia‐induced Igf1 upregulation in microglia
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20.3
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