Journal of Neuroinflammation | |
Impairing Gasdermin D-mediated pyroptosis is protective against retinal degeneration | |
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
【 预 览 】
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