Abstract
Retinal ischemia is a common pathological event that can result in retinal ganglion cell (RGC) death and irreversible vision loss. The pathogenic mechanisms linking retinal ischemia to RGC loss and visual deficits are uncertain, which has greatly hampered the development of effective treatments. It is increasingly recognized that pyroptosis of microglia contributes to the indirect inflammatory death of RGCs. In this study, we report a regulatory NOD-like receptor, NOD-, LRR- and CARD-containing 5 (NLRC5), as a key regulator on microglial pyroptosis and the retinal ischemia process. Through an in-depth analysis of our recently published transcriptome data, we found that NLRC5 was significantly up-regulated in retina during ischemia–reperfusion injury, which were further confirmed by subsequent detection of mRNA and protein level. We further found that NLRC5 was upregulated in retinal microglia during ischemia, while NLRC5 knockdown significantly ameliorated retinal ischemic damage and RGC death. Mechanistically, we revealed that knockdown of NLRC5 markedly suppressed gasdermin D (GSDMD) cleavage and activation of interleukin-1β (IL-1β) and caspase-3, indicating that NLRC5 promotes both microglial pyroptosis and apoptosis. Notably, we found that NLRC5 directly bound to NLRP3 and NLRC4 in inflammasomes to cooperatively drive microglial pyroptosis and apoptosis mediating retinal ischemic damage. Overall, these findings reveal a previously unidentified key contribution of NLRC5 signaling to microglial pyroptosis under ischemia or hypoxia conditions. This NLRC5-dependent pathway may be a novel therapeutic target for treatment of ischemic retinopathy.
Highlights
Ischemic retinopathy is one of the leading causes of visual impairment and irreversible blindness worldwide
By analyzing transcriptome sequencing data obtained from our recently published study (Chen et al, 2020), we discovered that the mRNA expression level of regulatory NLRC5 was significantly upregulated in the retina of retinal ischemia–reperfusion (RIR) injury model mice, and this upregulation was further confirmed by Real-time quantitative PCR (RT-qPCR) (Figures 1D,E)
We provide the first evidence that the regulatory NOD-like receptor NLRC5 is critically involved in elevated intraocular pressure (IOP)-induced retinal ischemic injury and retinal ganglion cell (RGC) death
Summary
Ischemic retinopathy is one of the leading causes of visual impairment and irreversible blindness worldwide. It is a common clinical entity associated with various ocular disorders in which retinal blood flow is insufficient to meet the metabolic demands of the retina (the highest of any tissue), including acute glaucoma, retinal vein occlusion, retinopathy of prematurity, and diabetic retinopathy (Hardy et al, 2005; Jo et al, 2015). While it is well known that interruption of retinal blood flow causes retinal ischemia–reperfusion (RIR) injury and eventually leads to NLRC5 Promotes Microglial Pyroptosis retinal ganglion cell (RGC) death (Fouda et al, 2018), molecular pathomechanisms of RGC death and associated treatment targets are still obscure. Our previous studies demonstrated that this microglia-driven neuroinflammation mediates retinal tissue damage and RGC death during RIR injury (Chi et al, 2014)
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