Abstract
Activation of the inflammasome is involved in the progression of retinal degenerative diseases, in particular, in the pathogenesis of Age-Related Macular Degeneration (AMD), with NLRP3 activation the focus of many investigations. In this study, we used genetic and pharmacological approaches to explore the role of the inflammasome in a mouse model of retinal degeneration. We identify that Casp1/11−/− mice have better-preserved retinal function, reduced inflammation and increased photoreceptor survivability. While Nlrp3−/− mice display some level of preservation of retinal function compared to controls, pharmacological inhibition of NLRP3 did not protect against photoreceptor cell death. Further, Aim2−/−, Nlrc4−/−, Asc−/−, and Casp11−/− mice show no substantial retinal protection. We propose that CASP-1-associated photoreceptor cell death occurs largely independently of NLRP3 and other established inflammasome sensor proteins, or that inhibition of a single sensor is not sufficient to repress the inflammatory cascade. Therapeutic targeting of CASP-1 may offer a more promising avenue to delay the progression of retinal degenerations.
Highlights
Age-Related Macular Degeneration (AMD) is a chronic inflammatory disease that is characterised by central vision loss due to retinal pigmented epithelium (RPE) and photoreceptor cell death in the macular region of the retina[1,2]
Results from this study demonstrate an important function of CASP-1 inflammasomes in mediating retinal degenerations, with Casp1/11−/− mice having significantly better-preserved retinal function, increased photoreceptor survivability, and decreased inflammation compared to controls
We showed that while Nlrp3−/− mice had some preservation of retinal function following photo-oxidative damage, WT mice injected intravitreally with either Nlrp[3] siRNA or specific inhibitor MCC950, showed decreased or unchanged retinal function compared to controls
Summary
Age-Related Macular Degeneration (AMD) is a chronic inflammatory disease that is characterised by central vision loss due to retinal pigmented epithelium (RPE) and photoreceptor cell death in the macular region of the retina[1,2]. To date studies using animal models have been focused on wet-AMD21, while those which investigate the role of NLRP3 in dry-AMD pathogenesis have been largely cell culture-based and focused on the RPE19,21,22,27,28,31,32 They demonstrate that the NLRP3 inflammasome can be activated in RPE by various stimulations such as oxidative stress[19], accumulation of repetitive transposable elements of non-coding RNA (Alu RNA)[22,32], or inflammatory pathway stimulants including drusen components lipofuscin[31], C1q21, or Aβ-peptide 1–4027,28; they do not provide any conclusive evidence to show NLRP3 involvement in AMD disease progression.
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