Involvement of the NLRC4 inflammasome in promoting retinal ganglion cell death in an acute glaucoma mouse model. (February 2021)

• Record Type: Journal Article
• Authors: Yao, Ke; Zhao, Yin; Jin, Peiming; Lou, Xiaotong; Luo, Zhaoxia; Zhang, Hong; Li, Fei
• Is Part Of: Experimental eye research. Volume 203(2021)
• Publication Date: 2021-02
• Subjects: NLRC4 inflammasome -- Retinal ischemia-reperfusion -- Acute glaucoma -- Adeno-associated virus 2; Ophthalmology -- Periodicals; Eye -- Periodicals; Œil -- Périodiques; Ophthalmology; Periodicals; Electronic journals; 612.8405
• DOI: 10.1016/j.exer.2020.108388
• Languages: English
• ISSNs: 0014-4835

Abstract

Abstract: Purpose: 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. Method: 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). Results: 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. Conclusion: 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. Highlights: 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.