Caspase-1 Inhibition Ameliorates Photoreceptor Damage Following Retinal Detachment by Inhibiting Microglial Pyroptosis

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.