The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia.
The ANU Medical School, The Australian National University, Canberra, ACT, Australia.
Sci Rep. 2020 Feb 10;10(1):2263. doi: 10.1038/s41598-020-58849-z.
Activation of the inflammasome is involved in the progression of retinal degenerative diseases, in particular, in the pathogenesis of Age-Related Macular Degeneration (AMD), with NLRP3 activation the focus of many investigations. In this study, we used genetic and pharmacological approaches to explore the role of the inflammasome in a mouse model of retinal degeneration. We identify that Casp1/11 mice have better-preserved retinal function, reduced inflammation and increased photoreceptor survivability. While Nlrp3 mice display some level of preservation of retinal function compared to controls, pharmacological inhibition of NLRP3 did not protect against photoreceptor cell death. Further, Aim2, Nlrc4, Asc, and Casp11 mice show no substantial retinal protection. We propose that CASP-1-associated photoreceptor cell death occurs largely independently of NLRP3 and other established inflammasome sensor proteins, or that inhibition of a single sensor is not sufficient to repress the inflammatory cascade. Therapeutic targeting of CASP-1 may offer a more promising avenue to delay the progression of retinal degenerations.
炎症小体的激活与视网膜退行性疾病的进展有关，特别是与年龄相关性黄斑变性（AMD）的发病机制有关，其中 NLRP3 的激活是许多研究的焦点。在这项研究中，我们使用遗传和药理学方法来探索炎症小体在视网膜变性小鼠模型中的作用。我们发现 Casp1/11 小鼠具有更好的视网膜功能保留、减少的炎症和增加的光感受器存活率。虽然 Nlrp3 小鼠与对照组相比显示出一定程度的视网膜功能保留，但 NLRP3 的药理学抑制不能防止光感受器细胞死亡。此外，Aim2、Nlrc4、Asc 和 Casp11 小鼠没有显示出实质性的视网膜保护作用。我们提出 CASP-1 相关的光感受器细胞死亡在很大程度上独立于 NLRP3 和其他已建立的炎症小体传感器蛋白发生，或者抑制单个传感器不足以抑制炎症级联反应。针对 CASP-1 的治疗可能提供更有前途的途径来延缓视网膜变性的进展。
