Impairing Gasdermin D-mediated pyroptosis is protective against retinal degeneration

Journal of Neuroinflammation

Research

Chinh Ngo¹  Melan Kurera¹  Si Ming Man¹  Riccardo Natoli²  Yvette Wooff²  Adrian V. Cioanca²  Rakshanya Sekar² 

[1] The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia;The John Curtin School of Medical Research, The Australian National University, Canberra, ACT, Australia;School of Medicine and Psychology, The Australian National University, Canberra, ACT, Australia;

关键词: Gasdermin D;    Age-related macular degeneration (AMD);    Retinal degenerations;    Neuroinflammation;    Inflammasome;    IL-1β;    Extracellular vesicles;   

DOI  :  10.1186/s12974-023-02927-2

 received in 2023-08-14, accepted in 2023-10-10,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundInflammasome activation and the subsequent release of pro-inflammatory cytokines including Interleukin 1β (IL-1β) have been widely reported to contribute to the progression of retinal degenerations, including age-related macular degeneration (AMD), the leading cause of blindness in the Western World. The role of Gasdermin D (GSDMD), a key executioner of pyroptosis following inflammasome activation, however, is less well-established. In this study we aimed to characterise the role of GSDMD in the healthy and degenerating retina, and uncover its role as a conduit for IL-1β release, including via extracellular vesicle (EV)-mediated release.MethodsGSDMD mutant and knockout mice, in vitro models of inflammation and a well-established in vivo model of retinal degeneration (photo-oxidative damage; PD) were utilised to explore the role and pathological contribution of GSDMD in regulating IL-1β release and propagating retinal inflammation. RNA sequencing of whole retinas was used to investigate GSDMD-mediated inflammation during degeneration. The role of EVs in GSDMD-mediated IL-1β release was investigated using nanoparticle tracking analysis, ELISA and EV inhibition paradigms. Finally, the therapeutic efficacy of targeting GSDMD was examined using GSDMD-specific siRNA.ResultsWe identified in this work that mice deficient in GSDMD had better-preserved retinal function, increased photoreceptor survivability and reduced inflammation. RNA-Seq analysis revealed that GSDMD may propagate inflammation in the retina via NF-κB signalling cascades and release of pro-inflammatory cytokines. We also showed that IL-1β was packaged and released via EV in a GSDMD-dependent manner. Finally, we demonstrated that impairing GSDMD function using RNAi or blocking EV release was able to reduce IL-1β content in cell-free supernatant and EV.ConclusionsTaken together, these results suggest that pyroptotic pore-forming protein GSDMD plays a key role in the propagation of retinal inflammation, in particular via the release of EV-encapsulated IL-1β. Targeting GSDMD using genetic or pharmacological inhibitors may pose a therapeutic opportunity to dampen inflammatory cascades and delay the progression of retinal degeneration.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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