NLRP12 collaborates with NLRP3 and NLRC4 to promote pyroptosis inducing ganglion cell death of acute glaucoma

Hui Chen,Lishi Su,Yizhi Liu,Jiawen Luo,Yang Deng,Lai Wei,Yonghao Li,Bin Zou,Yanhua Hong,Wei Chi,Yihai Cao,Xiaoliang Gan,Lin Lu,Wenyong Huang

doi:10.1186/s13024-020-00372-w

Abstract

BackgroundAcute glaucoma, characterized by a sudden elevation in intraocular pressure (IOP) and retinal ganglion cells (RGCs) death, is a major cause of irreversible blindness worldwide that lacks approved effective therapies, validated treatment targets and clear molecular mechanisms. We sought to explore the potential molecular mechanisms underlying the causal link between high IOP and glaucomatous RGCs death.MethodsA murine retinal ischemia/ reperfusion (RIR) model and an in vitro oxygen and glucose deprivation/reoxygenation (OGDR) model were used to investigate the pathogenic mechanisms of acute glaucoma.ResultsOur findings reveal a novel mechanism of microglia-induced pyroptosis-mediated RGCs death associated with glaucomatous vision loss. Genetic deletion of gasdermin D (GSDMD), the effector of pyroptosis, markedly ameliorated the RGCs death and retinal tissue damage in acute glaucoma. Moreover, GSDMD cleavage of microglial cells was dependent on caspase-8 (CASP8)-hypoxia-inducible factor-1α (HIF-1α) signaling. Mechanistically, the newly identified nucleotide-binding leucine-rich repeat-containing receptor (NLR) family pyrin domain-containing 12 (NLRP12) collaborated with NLR family pyrin domain-containing 3 (NLRP3) and NLR family CARD domain-containing protein 4 (NLRC4) downstream of the CASP8-HIF-1α axis, to elicit pyroptotic processes and interleukin-1β (IL-1β) maturation through caspase-1 activation, facilitating pyroptosis and neuroinflammation in acute glaucoma. Interestingly, processing of IL-1β in turn magnified the CASP8-HIF-1α-NLRP12/NLRP3/NLRC4-pyroptosis circuit to accelerate inflammatory cascades.ConclusionsThese data not only indicate that the collaborative effects of NLRP12, NLRP3 and NLRC4 on pyroptosis are responsible for RGCs death, but also shed novel mechanistic insights into microglial pyroptosis, paving novel therapeutic avenues for the treatment of glaucoma-induced irreversible vision loss through simultaneously targeting of pyroptosis.

Highlights

Acute glaucoma, characterized by a sudden elevation in intraocular pressure (IOP) and retinal ganglion cells (RGCs) death, is a major cause of irreversible blindness worldwide that lacks approved effective therapies, validated treatment targets and clear molecular mechanisms
Pyroptosis plays a key role in elevated IOP-induced retinal ischemic injury and glaucomatous RGCs death Pyroptosis is a novel inflammatory form of cell death triggered by CASP1/CASP11 and is characterized by membrane pore formation via the N-terminal fragment of gasdermin D (GSDMD) along with inflammatory cytokine leakage [19, 38]
These findings reveal that CASP1-mediated pyroptosis participates in retinal ischemia/ reperfusion (RIR) pathogenesis and is associated with RGCs death and retinal ischemic damage in acute glaucoma

Summary

Introduction

Acute glaucoma, characterized by a sudden elevation in intraocular pressure (IOP) and retinal ganglion cells (RGCs) death, is a major cause of irreversible blindness worldwide that lacks approved effective therapies, validated treatment targets and clear molecular mechanisms. We [7], Vargas et al [8] and many other scientists [9,10,11] have reported that high IOP-induced ischemia initiates microglial neuroinflammation that mediates retinal tissue damage and RGCs death. It is demonstrated that retinal ischemia directly induces RGCs death and triggers damage-associated molecular pattern (DAMP)-induced toll-like receptor 4 (TLR4) inflammasome-dependent neuroinflammation to activate the microglia, inducing further RGCs death [7, 12, 13]

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