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

Yao, Ke; Zhao, Yin; Jin, Peiming; Lou, Xiaotong; Luo, Ziyang; Zhang, Hong; Li, Fēi

doi:10.1016/j.exer.2020.108388

Cited by 7 publications

(3 citation statements)

References 47 publications

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“…Excessive glutamate interacts with the glutamate receptors on RGCs, resulting in a large Ca 2+ influx and mitochondrial dysfunction, thus triggering NLRP3 inflammasome activation that leads to RGC death [ 162 ]. Apart from the NLRP3 inflammasome, studies have shown that NLRC4 is also involved in RGC pyroptosis in an acute glaucoma mouse model, but the precise mechanism requires further investigation [ 163 ].…”

Section: Pyroptosis In Ocular Diseasesmentioning

confidence: 99%

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

Chen

Rong

Xia

2022

J Neuroinflammation

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Pyroptosis is a programmed cell death characterized by swift plasma membrane disruption and subsequent release of cellular contents and pro-inflammatory mediators (cytokines), including IL‐1β and IL‐18. It differs from other types of programmed cell death such as apoptosis, autophagy, necroptosis, ferroptosis, and NETosis in terms of its morphology and mechanism. As a recently discovered form of cell death, pyroptosis has been demonstrated to be involved in the progression of multiple diseases. Recent studies have also suggested that pyroptosis is linked to various ocular diseases. In this review, we systematically summarized and discussed recent scientific discoveries of the involvement of pyroptosis in common ocular diseases, including diabetic retinopathy, age-related macular degeneration, AIDS-related human cytomegalovirus retinitis, glaucoma, dry eye disease, keratitis, uveitis, and cataract. We also organized new and emerging evidence suggesting that pyroptosis signaling pathways may be potential therapeutic targets in ocular diseases, hoping to provide a summary of overall intervention strategies and relevant multi-dimensional evaluations for various ocular diseases, as well as offer valuable ideas for further research and development from the perspective of pyroptosis.

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Section: Pyroptosis In Ocular Diseasesmentioning

confidence: 99%

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

Chen

Rong

Xia

2022

J Neuroinflammation

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“…It acts as the processing unit to integrate the signals of pathogens, cell or tissue damage, and foreignness ( Di Virgilio, 2013 ). The human eye has a well-developed immune surveillance system that can help fight against various pathogens, involving the contribution of NLRP1, NLRP3, NLRC4, NLRP12, and AIM2 inflammasomes ( Gu et al, 2019 ; Pronin et al, 2019 ; Chen et al, 2020b ; Lyon et al, 2020 ; Jassim et al, 2021 ; Yao et al, 2021 ). Unlike the protective effect of activated inflammasomes in combating pathogens in other tissue infections, such as infections of the lung with Mycobacterium tuberculosis , the activated inflammasomes in ocular diseases lead to increased severity of inflammation and more serious tissue destruction ( Master et al, 2008 ; Akhtar-Schäfer et al, 2018 ).…”

Section: Ocular Diseases Inflammasomes and Pyroptosismentioning

confidence: 99%

Pyroptosis: A New Insight Into Eye Disease Therapy

Zhang

Yan

et al. 2021

Front. Pharmacol.

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Pyroptosis is a lytic form of programmed cell death mediated by gasdermins (GSDMs) with pore-forming activity in response to certain exogenous and endogenous stimuli. The inflammasomes are intracellular multiprotein complexes consisting of pattern recognition receptors, an adaptor protein ASC (apoptosis speck-like protein), and caspase-1 and cause autocatalytic activation of caspase-1, which cleaves gasdermin D (GSDMD), inducing pyroptosis accompanied by cytokine release. In recent years, the pathogenic roles of inflammasomes and pyroptosis in multiple eye diseases, including keratitis, dry eyes, cataracts, glaucoma, uveitis, age-related macular degeneration, and diabetic retinopathy, have been continuously confirmed. Inhibiting inflammasome activation and abnormal pyroptosis in eyes generally attenuates inflammation and benefits prognosis. Therefore, insight into the pathogenesis underlying pyroptosis and inflammasome development in various types of eye diseases may provide new therapeutic strategies for ocular disorders. Inhibitors of pyroptosis, such as NLRP3, caspase-1, and GSDMD inhibitors, have been proven to be effective in many eye diseases. The purpose of this article is to illuminate the mechanism underlying inflammasome activation and pyroptosis and emphasize its crucial role in various ocular disorders. In addition, we review the application of pyroptosis modulators in eye diseases.

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“…Olaparib is a PARP inhibitor that inhibits both PARP-1 and PARP-2 activities. Recent studies have shown that olaparib protects neuronal cells by inhibiting inflammasome activation (Sethi et al, 2019;Yao et al, 2021). Both in vitro and in vivo experiments have shown that olaparib protects photoreceptors in mice with retinitis pigmentosa by inhibiting PARP-1-dependent cell death (Sahaboglu et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Olaparib, a PARP-1 inhibitor, protects retinal cells from ocular hypertension-associated oxidative damage

Yang

Lü

et al. 2022

Front. Cell Dev. Biol.

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Glaucoma is the most common cause of irreversible blindness worldwide. Elevated intraocular pressure (IOP) and relative hypoxia in the retina stimulate the production of reactive oxygen species (ROS), which, in turn, puts the retina and optic nerve under chronic oxidative stress. Emerging evidence has shown that oxidative stress can trigger PARP-1 overactivation, mitochondrial-associated endoplasmic reticulum membrane (MAM) dysregulation, and NLRP3 activation. Oxidative damage can trigger inflammasome activation, and NLRP3 is the only inflammasome associated with MAM dysregulation. In addition, multiple transcription factors are located on the MAM. This study aimed to investigate the protective effects and underlying mechanisms of a PARP-1 inhibitor (olaparib) against chronic ocular hypertension-associated retinal cell damage. We also mimicked hypoxic stimulation of a retinal precursor cell line by exposing the cells to 0.2% O2in vitro. We discovered that chronic ocular hypertension (COH) induces oxidative damage and MAM dysregulation in the retinal ganglion cells (RGCs). The protein levels of cleaved-PARP and NLRP3 were upregulated in the retinas of the COH rats. Olaparib, a PARP-1 inhibitor, alleviated COH-induced RGC loss, retinal morphological alterations, and photopic negative response amplitude reduction. Olaparib also relieved hypoxic stimulation-induced loss of cell viability and MAM dysregulation. Additionally, some indicators of mitochondrial performance, such as reactive oxygen species accumulation, mitochondrial Ca2+ influx, and mitochondrial membrane potential collapse, decreased after olaparib treatment. Olaparib attenuated the hypoxia-induced upregulation of NLRP3 protein levels as well as the phosphorylation of ERK1/2 and histone H2A.X. These results suggest that olaparib protects RGCs from chronic intraocular pressure elevation in vivo and alleviates the abnormal MAM dysregulation and mitochondrial dysfunction caused by hypoxia in vitro. This protection may be achieved by inhibiting PARP-1 overactivation, NLRP3 upregulation, and phosphorylation of ERK1/2.

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

Cited by 7 publications

References 47 publications

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

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

Pyroptosis: A New Insight Into Eye Disease Therapy

Olaparib, a PARP-1 inhibitor, protects retinal cells from ocular hypertension-associated oxidative damage

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