Department of Ophthalmology, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou First People's Hospital, Eye Disease Prevention and Treatment Institute of Xuzhou, Xuzhou, China; Xuzhou Medical University, Xuzhou, China.
Central Laboratory, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou First People's Hospital, Eye Disease Prevention and Treatment Institute of Xuzhou, Xuzhou, China.
Am J Pathol. 2024 Oct;194(10):1924-1937. doi: 10.1016/j.ajpath.2024.06.009. Epub 2024 Jul 18.
Retinal detachment (RD) is a sight-threatening condition that occurs in several retinal diseases. Microglia that reside in retina are activated after RD and play a role in the death of photoreceptor cells. The involvement of microglial pyroptosis in the early pathological process of RD is still unclear. VX-765, an inhibitor of caspase-1, may exert neuroprotective effects by targeting microglial pyroptosis in nervous system disease; however, whether it plays a role in RD is uncertain. This study detected and localized pyroptosis to specific cells by immunofluorescence co-staining and flow cytometry in rat RD models. The majority of gasdermin D N-terminal (GSDMD-N)-positive cells exhibited IBA1-positive or P2RY12-positive microglia in the early stage of RD, indicating the pyroptosis of microglia. Administration of VX-765 shifted the microglia phenotype from M1 to M2, inhibited microglial migration toward the outer nuclear layer (ONL) post-RD, and most importantly, inhibited microglial pyroptosis. The thickness of ONL increased with VX-765 administration, and the photoreceptors were more structured and orderly under hematoxylin and eosin staining and transmission electron microscopy, revealing the protective effects of VX-765 on photoreceptors. Overall, this study demonstrated that inflammation induced by pyroptosis of microglia is the early pathological process of RD. VX-765 may serve as a candidate therapeutic approach for the treatment of RD by targeting microglia.
视网膜脱离（RD）是一种发生在几种视网膜疾病中的致盲性疾病。RD 后，驻留在视网膜中的小胶质细胞被激活，并在光感受器细胞死亡中发挥作用。小胶质细胞细胞焦亡在 RD 的早期病理过程中的参与尚不清楚。Caspase-1 的抑制剂 VX-765 可能通过靶向神经退行性疾病中的小胶质细胞细胞焦亡发挥神经保护作用；然而，它在 RD 中是否发挥作用尚不确定。本研究通过免疫荧光共染色和流式细胞术在大鼠 RD 模型中检测并定位焦亡到特定细胞。在 RD 的早期阶段，大多数 Gasdermin D N 端（GSDMD-N）阳性细胞表现出 IBA1 阳性或 P2RY12 阳性小胶质细胞，表明小胶质细胞发生了细胞焦亡。VX-765 的给药将小胶质细胞表型从 M1 转变为 M2，抑制 RD 后小胶质细胞向核层（ONL）的迁移，最重要的是，抑制小胶质细胞细胞焦亡。随着 VX-765 的给药，ONL 的厚度增加，苏木精和伊红染色和透射电镜下的光感受器更具结构和有序，表明 VX-765 对光感受器具有保护作用。总体而言，这项研究表明，小胶质细胞细胞焦亡引起的炎症是 RD 的早期病理过程。VX-765 可能通过靶向小胶质细胞成为治疗 RD 的候选治疗方法。
