The Regulatory NOD-Like Receptor NLRC5 Promotes Ganglion Cell Death in Ischemic Retinopathy by Inducing Microglial Pyroptosis

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.

microRNAs Control Antiviral Immune Response, Cell Death and Chemotaxis Pathways in Human Neuronal Precursor Cells (NPCs) during Zika Virus Infection

“…Next, we investigated genes involved in cell death that could be putative targets of miR-302b, miR-302c and miR-194 in ZIKV-infected hiNPCs (NCBI BioProject PRJNA551246). We found increased levels of NLRC5 (NLR Family CARD Domain Containing 5), a molecule that acts both as a transcriptional activator of MHCI, and also a Pattern Recognition Receptor (PRRs) already shown to be important for ant-viral responses [ 30 ], and CASP1 (Caspase-1), which together can induce cell death by pyroptosis [ 31 ]. Other genes involved in cell death pathways were also upregulated by ZIKV, such as: TLR3 , CD274 , TNFSF10 , GBP1 , PMAIP1 , PDC1LG2 , and MLKL ( Figure 3 A,B).…”

Spotlight on pyroptosis: role in pathogenesis and therapeutic potential of ocular diseases

“…The regulatory function of NLRC5 in microglial pyroptosis also relies on its cooperation with NLRP3 and NLRC4 in high intraocular pressure (IOP)-induced ischemic retinopathy. Neurotoxic factors secreted by microglia in response to pyroptosis further harm RGCs and cause irreversible damage [ 66 ].…”

Microglia Polarization: A Novel Target of Exosome for Stroke Treatment

“…In pMCAO mice, dexmedetomidine inhibited microglia pyroptosis by acting on the P2X7R/NLRP3/Caspase-1 signaling pathway and play a protective role in ischemic brain injury ( Sun et al, 2021 ). In retinal ischemic injury, a NOD-like receptor named NLR caspase recruitment domain (CARD) containing 5 (NLRC5) was identified, which binds to the inflammasome NLRP3 and NLR-family CARD-containing protein 4 (NLRC4) and mediates microglial cell pyroptosis ( Deng et al, 2021 ). In addition, in spinal cord injury, CD73 may inhibit the activation of the NLRP3 inflammasome complex through the adenosine-A2B adenosine receptor- phosphoinositide 3-kinase (PI3K)-AKT-Foxo1 cascade, reducing the activation of gasdermin D and thus microglia pyroptosis ( Xu et al, 2021 ).…”