PDF(Pubmed)
Abstract：
Retinal ischemia, after cerebral ischemia, is an easily overlooked pathophysiological problem in which inflammation is considered to play an important role. Pyroptosis is a kind of cell death pattern accompanied by inflammation. Homer scaffold protein 1 (Homer1) has anti-inflammation properties and protects against ischemic injury. However, little is known about pyroptosis following middle cerebral artery occlusion (MCAO)-induced retinal ischemia and the regulatory mechanisms involved by Homer1 for the development of pyroptosis. In the present study, retinal ischemic injury was induced in mice by permanent MCAO in vivo, and retinal ganglion cells (RGCs) were subjected to Oxygen and Glucose Deprivation (OGD) to establish an in vitro model. It was shown that TXNIP/NLRP3-mediated pyroptosis was located predominantly in RGCs, which gradually increased after retinal ischemia and peaked at 24 h after retinal ischemia. Interestingly, the RGCs pyroptosis occurred not only in the cell body but also in the axon. Notably, the occurrence of pyroptosis coincided with the change of Homer1 expression in the retina after retinal ischemia and Homer1 also co-localized with RGCs. It was demonstrated that overexpression of Homer1 not only alleviated RGCs pyroptosis and inhibited the release of pro-inflammatory factors but also led to the increase in phosphorylation of AMPK, inhibition of ER stress, and preservation of visual function after retinal ischemia. In conclusion, it was suggested that Homer1 may protect against MCAO-induced retinal ischemia and RGCs pyroptosis by inhibiting endoplasmic reticulum stress-associated TXNIP/NLRP3 inflammasome activation after MCAO-induced retinal ischemia.
摘要：
视网膜缺血,脑缺血后，是一个容易被忽视的病理生理问题，其中炎症被认为起着重要作用。焦亡是一种伴随炎症的细胞死亡模式。Homer支架蛋白1（Homer1）具有抗炎特性，可防止缺血性损伤。然而,关于大脑中动脉阻塞（MCAO）诱导的视网膜缺血后的焦亡以及Homer1参与焦亡发展的调节机制知之甚少。在本研究中,小鼠体内永久性MCAO诱发视网膜缺血性损伤，和视网膜神经节细胞（RGCs）进行氧糖剥夺（OGD）以建立体外模型。研究表明，TXNIP/NLRP3介导的焦亡主要位于RGC中，在视网膜缺血后逐渐增加，并在视网膜缺血后24h达到峰值。有趣的是,RGC的焦亡不仅发生在细胞体中，也发生在轴突中。值得注意的是,焦亡的发生与视网膜缺血后视网膜中Homer1表达的变化同时发生，并且Homer1也与RGCs共定位。研究表明，Homer1的过表达不仅减轻了RGCs的细胞凋亡，抑制了促炎因子的释放，而且导致AMPK的磷酸化增加，抑制ER应激，视网膜缺血后视觉功能的保护。总之,提示Homer1可能通过抑制MCAO诱导的视网膜缺血后的内质网应激相关的TXNIP/NLRP3炎性体激活来保护MCAO诱导的视网膜缺血和RGCs的焦亡。
