Hypobaric hypoxia triggers pyroptosis in the retina via NLRP3 inflammasome activation

Xin, Xiaorong; Yang, Kun; Li, Haiping; Li, Yanrong

doi:10.1007/s10495-022-01710-7

Cited by 13 publications

(9 citation statements)

References 54 publications

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“…Moreover, caspase‐1 also cleaves gasdermin D, inducing plasma membrane pore formation and the release of cytoplasmic contents, culminating in pyroptosis. Critical to pyroptosis is the NLRP3 inflammasome, where NLRP3 and ASC orchestrate caspase‐1 activation 33 . Our results indicated that OGD/R upregulated activated caspase‐1, NLRP3, ASC, C‐caspase‐1, and GSDMD‐N in RPE cells, indicative of pyroptosis initiation.…”

Section: Discussionmentioning

confidence: 67%

“…Additionally, pyroptosis, characterized by the release of inflammatory cytokines such as IL‐1beta, IL‐6, and IL‐18, plays a substantial role in immune responses, inflammation, and diseases like neurodegeneration, cancer, and autoimmunity 33 . Pyroptosis plays a crucial role in the immune response to infections by promoting the release of pro‐inflammatory cytokines and inducing inflammatory cell death.…”

Section: Discussionmentioning

confidence: 99%

“…Pyroptosis appears to play a role in I/R injury‐induced RPE cell death, as evidenced by the increased expression of key components of the pyroptosis pathway such as NLRP3, ASC, and caspase‐1 in damaged RPE cells. GSDMD has also been implicated in I/R injury‐induced RPE cell death 33–35 . Although there is currently no evidence linking PLD to the regulation of I/R injury‐induced pyroptosis, targeting pyroptosis has been shown to alleviate I/R injury, suggesting that it represents a potential therapeutic approach for reducing retinal damage and preserving visual function in I/R injury.…”

Section: Introductionmentioning

confidence: 99%

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OGD/R‐induced ferroptosis and pyroptosis in retinal pigment epithelium cells: Role of PLD1 and PLD2 modulation

Park,

Kang,

Park

et al. 2023

Cell Biochemistry & Function

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This study investigated the role of phospholipase D (PLD) in retinal ischemia–reperfusion (I/R) injury using an oxygen‐glucose deprivation/reperfusion (OGD/R) model commonly used in retinal I/R injury research. To create an in vitro cellular I/R model, pharmacological inhibitors and small interfering RNA (siRNA) were used to target PLD1 and PLD2 in retinal pigment epithelial (RPE) cells. Treatment with PLD inhibitors and siRNA reduced reactive oxygen species (ROS) and malondialdehyde (MDA) induced by OGD/R in RPE cells and increased the levels of superoxide dismutase (SOD) and glutathione (GSH), indicating a reduction in oxidative damage and improvement in the antioxidant system. Next, we showed that inhibiting PLD1 or PLD2 reduced intracellular iron levels and lipid peroxidation, which are critical factors in ferroptosis. Additionally, PLD1 and PLD2 modulated the expression of proteins involved in the regulation of ferroptosis, including GPX4, SLC7A11, FTH1, and ACSL4. We also investigated the roles of PLD1 and PLD2 in preventing pyroptosis, another form of programmed cell death associated with inflammation. Our study found that OGD/R significantly increased the production of pro‐inflammatory cytokines and activated caspase‐1, NLRP3, ASC, cleaved‐caspase 1 (C‐caspase‐1), and GSDMD‐N in RPE cells, indicating pyroptosis induction. However, PLD1 and PLD2 inhibition or knockdown significantly inhibited the production of pro‐inflammatory cytokines and activation of the NLRP3 inflammasome, Taken together, our findings support the hypothesis that the PLD signaling pathway plays a key role in OGD/R‐induced ferroptosis and pyroptosis induction and may be a potential therapeutic target for preventing or treating retinal dysfunction and degeneration.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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OGD/R‐induced ferroptosis and pyroptosis in retinal pigment epithelium cells: Role of PLD1 and PLD2 modulation

Park,

Kang,

Park

et al. 2023

Cell Biochemistry & Function

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“…The first step in pyroptosis involves inflammasome assembly and activation. The intimate link between hypoxia and NLRP3 inflammation has been well described [31][32][33][34]. Hypoxia/reoxygenation activates NLRP3 inflammasome-mediated pyroptosis by upregulating reactive oxygen species (ROS) production [35].…”

Section: Discussionmentioning

confidence: 99%

Disulfiram attenuates hypoxia-induced pulmonary hypertension by inhibiting GSDMD cleavage and pyroptosis in HPASMCs

Wang

et al. 2022

Respir Res

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Background Pulmonary hypertension (PH) is characterized by progressive pulmonary arterial remodelling, associated with different severities of inflammation and altered immune processes. Disulfiram eliminates the formation of N-gasdermin D (GSDMD) plasma membrane pores to prevent pyroptosis. Pyroptosis is a form of lytic cell death characterized by inflammasome activation and proinflammatory cytokine release that acts in the development of PH. We sought to investigate whether disulfiram could alleviate hypoxia-induced PH by inhibiting pyroptosis. Methods To investigate whether disulfiram alleviates the progression of pulmonary hypertension, rodents were exposed to chronic hypoxia (10% oxygen, 4 weeks) to induce PH. The severity of PH was assessed by measuring right ventricular systolic pressure, mean pulmonary artery pressure, and the degree of right ventricular hypertrophy. Western blotting was used to measure proteins associated with the pyroptosis pathway, and ELISA was performed to measure the secretion of IL-18 and IL-1β, both of which are the primary methods for assessing pyroptosis. Results IL-18 and IL-1β concentrations were higher in patients with PH than in normal controls. Disulfiram suppressed the progression of PH in mice and rats through the alleviation of pulmonary arterial remodelling. Pyroptosis-related proteins and the inflammasome were activated in rodent models of PH. Disulfiram inhibited the processing of GSDMD into N-GSDMD and attenuated the secretion of IL-1β and IL18. In vivo experiments showed that disulfiram also inhibited lytic death in HPASMCs. Conclusions Disulfiram treatment reduces PH progression through suppressing vascular remodelling by inhibiting GSDMD cleavage and pyroptosis. It might become a novel therapeutic option for the treatment of PH.

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“…Unlike apoptosis and autophagy, pyroptosis is a pro-inflammatory form of RCD, characterized by cell swelling, membrane rupture, and inflammatory cytokine release 21 . Pyroptosis is initiated by activation of the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome complex 22 .…”

Section: Introductionmentioning

confidence: 99%

Targeting Necroptosis: A Novel Therapeutic Option for Retinal Degenerative Diseases

Zhang¹,

Hu²,

Zhao³

et al. 2023

Int. J. Biol. Sci.

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The discovery of the necroptosis, a form of regulated necrosis that is mediated by receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed-lineage kinase domain-like pseudokinase (MLKL), represents a major breakthrough that has dramatically altered the conception of necrosis -traditionally thought of as uncontrolled cell death -in various human diseases. Retinal cell death is a leading cause of blindness and has been identified in most retinal diseases, e.g., age-related macular degeneration, glaucoma, retinal detachment, retinitis pigmentosa, etc. Increasing evidence demonstrates that retinal degenerative diseases also share a common mechanism in necroptosis. Exacerbated necroptotic cell death hinders the treatment for retinal degenerative diseases. In this review, we highlight recent advances in identifying retinal necroptosis, summarize the underlying mechanisms of necroptosis in retinal degenerative diseases, and discuss potential anti-necroptosis strategies, such as selective inhibitors and chemical agents, for treating retinal degenerative diseases.

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Hypobaric hypoxia triggers pyroptosis in the retina via NLRP3 inflammasome activation

Cited by 13 publications

References 54 publications

OGD/R‐induced ferroptosis and pyroptosis in retinal pigment epithelium cells: Role of PLD1 and PLD2 modulation

OGD/R‐induced ferroptosis and pyroptosis in retinal pigment epithelium cells: Role of PLD1 and PLD2 modulation

Disulfiram attenuates hypoxia-induced pulmonary hypertension by inhibiting GSDMD cleavage and pyroptosis in HPASMCs

Targeting Necroptosis: A Novel Therapeutic Option for Retinal Degenerative Diseases

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