Molecular Endocrinology Group and the Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina; Department of Biology, Allegheny College, Meadville, Pennsylvania.
Molecular Endocrinology Group and the Signal Transduction Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.
Am J Pathol. 2024 Oct;194(10):1938-1950. doi: 10.1016/j.ajpath.2024.06.005.
The cornea protects the interior of the eye from external agents such as bacteria, viruses, and debris. Synthetic glucocorticoids are widely prescribed in the treatment of ocular infections and disorders. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR); however, the molecular and physiological functions of GR signaling in the cornea are poorly understood. This study found that treatment of mice with glucocorticoid eye drops led to a profound regulation of the corneal transcriptome. These glucocorticoid-regulated genes were associated with multiple biological functions, including the immune response. To understand the direct role of GR signaling in the cornea, mice with conditional knockout of GRs in the corneal epithelium were generated. Mice lacking corneal GRs exhibited microphthalmia, loss of pupils, a deformed and opaque lens, and mislocalization of key structural proteins within the corneal epithelial layers. Global transcriptomic approaches revealed that loss of GR signaling in the cornea also resulted in the dysregulation of a large cohort of genes strongly associated with an enhanced inflammatory response. Finally, corneal GR signaling was required for preventing neovascularization of blood and lymphatic vessels and thereby immune cell infiltration of the cornea. These results reveal that corneal GR signaling plays a critical role in ocular development and in maintaining the homeostasis of the eye.
角膜可保护眼球内部免受细菌、病毒和异物等外部因素的侵害。合成糖皮质激素被广泛用于治疗眼部感染和疾病。糖皮质激素的作用是通过糖皮质激素受体（GR）介导的；然而，GR 信号在角膜中的分子和生理功能仍知之甚少。本研究发现，用糖皮质激素眼药水治疗小鼠会导致角膜转录组发生深刻变化。这些糖皮质激素调节的基因与多种生物学功能有关，包括免疫反应。为了了解 GR 信号在角膜中的直接作用，生成了角膜上皮细胞中 GR 条件性敲除的小鼠。缺乏角膜 GR 的小鼠表现出小眼症、瞳孔丧失、晶状体变形和不透明以及角膜上皮层内关键结构蛋白的定位错误。全基因组转录组方法显示，角膜 GR 信号的缺失也导致与增强的炎症反应强烈相关的一大群基因的失调。最后，角膜 GR 信号对于防止血管和淋巴管的新生血管形成以及免疫细胞浸润角膜是必需的。这些结果表明，角膜 GR 信号在眼部发育和维持眼睛的内稳态中起着关键作用。
