Involvement of the NLRC4 inflammasome in promoting retinal ganglion cell death in an acute glaucoma mouse model

Abstract

To explore the role of nucleotide-binding oligomerization domain-like receptors (NLRs) family caspase-activation and the recruitment domain containing 4 (NLRC4) inflammasome in retinal ganglion cell (RGC) injury induced by an acute glaucoma mouse model. A mouse model of acute ocular hypertension, which can lead to retinal ischemia-reperfusion (I/R) injury, was established. The expression level of NLRC4 was detected by polymerase chain reaction and western blotting. Localized expression of NLRC4 was detected by examining immunofluorescence in eyeball sections. Intravitreal adeno-associated virus 2(AAV2) administration was used to knockdown retinal Nlrc4 . Fluoro-Gold labeled RGCs and TdT-mediated dUTP nick end labeling were used to evaluate the survival and apoptosis of RGCs. Tlr4 −/− mice were utilized to explore whether NLRC4 inflammasome is influenced by Toll-like receptor4 (TLR4). NLRC4, expressed in RGCs and microglial cells, was actively involved in mouse retinal I/R injury. Knockdown of Nlrc4 using an AAV2 vector caused an obvious reduction in the generation of IL-1β led by the rapidly elevated intraocular pressure, and thereby improved the RGC survival. In addition, activation of the NLRC4 inflammasome could influence the phosphorylation of p38 and Jun N-terminal kinase, which was largely dependent on TLR4 signaling. Our study demonstrated the role of NLRC4 inflammasome in promoting RGC damage in mouse retinal I/R injury. Inhibition of NLRC4 might be leveraged as a potential therapeutic target in glaucomatous retinopathy. • The NLRC4 inflammasome was activated in elevated IOP-induced RGC death. • The NLRC4 inflammasome activation was dependent on TLR4 signaling largely. • The NLRC4 inflammasome activation influenced the phosphorylation of p38 and JNK. • Viral knockdown of NLRC4 could act via a non-microglial pathway and benefit RGC survival after retinal I/R injury.

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