The NLRP3 inflammasome inhibitor OLT1177 attenuates retinal neovascularization and microglial inflammation with neuroprotective effects.

Abstract

Nucleotide-binding oligomerization domain like receptor protein 3 (NLRP3) inflammasome is considered as a critical contributor to pathological angiogenesis and neuronal dysfunction. However, its role in ischemic retinopathies remains unclear. In this study, we aimed to evaluate the role of NLRP3 inflammasome in ischemic retinopathies and the effects of the NLRP3 inflammasome inhibitor OLT1177 on retinal neovascularization (RNV) and neuronal dysfunction in a mouse model of oxygen induced retinopathy (OIR). A single-cell transcriptome analysis was performed using public data from the preretinal proliferative membranes in patients suffering from proliferative diabetic retinopathy (PDR), which was verified by immunofluorescence and western blot. The OIR mouse model was established, with OLT1177 being intravitreally injected on postnatal day 12. The effects of OLT1177 on RNV, neuronal loss and the activation of NLRP3 inflammasome were explored. Our results demonstrated that the NLRP3 inflammasome and associated inflammatory responses were observed within microglia in both the preretinal proliferative membranes of PDR patients and the retinas of OIR mice. OLT1177 attenuated pathological RNV at a concentration of 100 μM. Furthermore, OLT1177 reduced the neuronal loss and maintained the astrocytic framework in the non-perfusion areas of retinas. Microglial activation and NLRP3 inflammasome-associated microglial inflammation were alleviated in the OLT1177-treated mice. In conclusion, NLRP3 inflammasome activation and microglial inflammation occurred in ischemic retinopathies and the inhibitor OLT1177 was well-tolerated and beneficial in attenuating RNV and preventing neuronal death in the retinas of OIR mice, which indicated that OLT1177 might be a promising treatment option for ischemic retinopathies.