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

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.

• Authors: Ke Yao, Yin Zhao, Peiming Jin, Xiaotong Lou, Zhaoxia Luo, Hong Zhang, Fei Li
• Journal: Experimental eye research (Exp Eye Res) Vol. 203 Pg. 108388 (02 2021) ISSN: 1096-0007 [Electronic] England
• PMID: 33333046 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Apoptosis Regulatory Proteins
• Calcium-Binding Proteins
• Inflammasomes
• Ipaf protein, mouse
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• p38 Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4

Topics

• Acute Disease
• Animals
• Apoptosis Regulatory Proteins (physiology)
• Blotting, Western
• Calcium-Binding Proteins (physiology)
• Cell Death (physiology)
• Dependovirus
• Disease Models, Animal
• Glaucoma (metabolism, pathology)
• In Situ Nick-End Labeling
• Inflammasomes (metabolism)
• Intraocular Pressure
• MAP Kinase Kinase 4 (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Microscopy, Fluorescence
• Ocular Hypertension (metabolism, pathology)
• Parvovirinae (genetics)
• Phosphorylation
• Real-Time Polymerase Chain Reaction
• Reperfusion Injury (metabolism)
• Retina (metabolism)
• Retinal Ganglion Cells (metabolism, pathology)
• Toll-Like Receptor 4 (genetics, metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)