Yao Yao, Xu Yanxuan, Liang Jia-Jian, Zhuang Xi, Ng Tsz Kin
Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou, Guangdong, China; Shantou University Medical College, Shantou, Guangdong, China.
Joint Shantou International Eye Center of Shantou University and The Chinese University of Hong Kong, Shantou, Guangdong, China.
Exp Eye Res. 2022 Sep;222:109159. doi: 10.1016/j.exer.2022.109159. Epub 2022 Jun 23.
Retinal ganglion cell (RGC) death is a critical pathological trigger leading to irreversible visual impairment and blindness after optic nerve (ON) injury. Yet, there is still no effective clinical treatment to rescue RGC death after ON injury. Understanding the involvement of different modes of cell death post-ON injury could facilitate the development of targeting treatments against RGC death. Herein we aimed to characterize the regulation of 11 modes of cell death simultaneously and longitudinally in mouse retina post-ON injury. The number of RGCs gradually decreased from Day 3-14 in mice post-ON injury. Increase in the apoptosis (cleaved caspase-3), autolysis (cleaved cathespin B) and pyroptosis (cleaved caspase-1) marker expression in the retina began at Day 3 post-ON injury. Meanwhile, the markers for autophagy (Atg7 and Becn1) and phagocytosis (Mfge8 and Mertk) were downregulated from Day 1 to Day 5. Additionally, the expression of ferroptosis marker (4-hydroxynonenal) was upregulated from Day 7 to Day 14 post-ON injury following the early reduction of Gpx4. Yet, the reduction of parthanatos, sarmoptosis, and mitochondrial permeable transition could be related to autophagy and apoptosis. The markers for necroptosis did not show significant changes post-ON injury. In summary, this study revealed that the activation of apoptosis, autolysis, pyroptosis and ferroptosis, together with the early downregulation of autophagy and phagocytosis, are the major modes of cell death involved in the RGC death post-ON injury. Simultaneously targeting multiple modes of cell death at different time courses could be a potential treatment approach against RGC death for traumatic optic neuropathy.
视网膜神经节细胞（RGC）死亡是视神经（ON）损伤后导致不可逆视力损害和失明的关键病理触发因素。然而，目前仍没有有效的临床治疗方法来挽救ON损伤后的RGC死亡。了解ON损伤后不同细胞死亡模式的参与情况可能有助于开发针对RGC死亡的靶向治疗方法。在此，我们旨在同时纵向表征小鼠视网膜ON损伤后11种细胞死亡模式的调控情况。ON损伤后小鼠视网膜中的RGC数量从第3天到第14天逐渐减少。视网膜中凋亡（裂解的半胱天冬酶-3）、自溶（裂解的组织蛋白酶B）和焦亡（裂解的半胱天冬酶-1）标志物表达的增加在ON损伤后第3天开始。同时，自噬（Atg7和Becn1）和吞噬作用（Mfge8和Mertk）的标志物从第1天到第5天下调。此外，在Gpx4早期减少后，铁死亡标志物（4-羟基壬烯醛）的表达在ON损伤后第7天到第14天上调。然而，PARP-1依赖性坏死、溶酶体膜通透性增加介导的细胞死亡和线粒体通透性转变的减少可能与自噬和凋亡有关。坏死性凋亡标志物在ON损伤后未显示出显著变化。总之，本研究表明，凋亡、自溶、焦亡和铁死亡的激活，以及自噬和吞噬作用的早期下调，是ON损伤后RGC死亡所涉及的主要细胞死亡模式。在不同时间进程同时靶向多种细胞死亡模式可能是一种针对创伤性视神经病变RGC死亡的潜在治疗方法。
