| First Author | Sekar R | Year | 2023 |
| Journal | J Neuroinflammation | Volume | 20 |
| Issue | 1 | Pages | 239 |
| PubMed ID | 37864169 | Mgi Jnum | J:357934 |
| Mgi Id | MGI:7544468 | Doi | 10.1186/s12974-023-02927-2 |
| Citation | Sekar R, et al. (2023) Impairing Gasdermin D-mediated pyroptosis is protective against retinal degeneration. J Neuroinflammation 20(1):239 |
| abstractText | BACKGROUND: Inflammasome activation and the subsequent release of pro-inflammatory cytokines including Interleukin 1beta (IL-1beta) 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-1beta release, including via extracellular vesicle (EV)-mediated release. METHODS: GSDMD 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-1beta 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-1beta 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. RESULTS: We 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-kappaB signalling cascades and release of pro-inflammatory cytokines. We also showed that IL-1beta 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-1beta content in cell-free supernatant and EV. CONCLUSIONS: Taken 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-1beta. Targeting GSDMD using genetic or pharmacological inhibitors may pose a therapeutic opportunity to dampen inflammatory cascades and delay the progression of retinal degeneration. |
