Rapamycin Inhibits Light-Induced Necrosome Activation Occurring in Wild-Type, but not RPE65-Null, Mouse Retina

Abstract

Purpose Both photodamage and aberrant visual cycle contribute to disease progress of many retinal degenerative disorders, whereas the signaling pathways causing photoreceptor death remain unclear. Here we investigated the effects of intense photo-stress on (1) necrosome activation in wild-type and RPE65-null mice, (2) interaction of p62/Sequestosome-1 with the necrosome proteins, and (3) the effects of rapamycin on photodamage-induced necrosome activation and retinal degeneration in wild-type mice. Methods Dark-adapted rd 12 mice and 129S2/Sv mice with or without rapamycin treatment were exposed to 15,000 lux light for different times. Expression levels and subcellular localization of proteins were determined through immunoblot and immunohistochemical analyses. Cone sheaths were stained with peanut agglutinin. Correlation between photoreceptor degeneration and receptor-interacting protein kinase-1 (RIPK1) expression was assessed with Spearman's correlation analysis. Protein-protein interaction was analyzed by immunoprecipitation. Results Intense light caused rod and cone degeneration accompanied by a significant increase in RIPK1-RIPK3 expressions, mixed lineage kinase domain-like protein phosphorylation, damage-associated molecular patterns protein release, and inflammatory responses in wild-type mouse retina. The same intense light did not induce the necrosome activation in rd 12 retina, but it did in rd 12 mice that received 9- cis -retinal supply. RIPK1 expression levels are positively correlated with the degrees of rod and cone degeneration. Photodamage upregulated expression and interaction of the p62 autophagosome cargo protein with the necrosome proteins, whereas rapamycin treatment attenuated the light-induced necrosome activation and photoreceptor degeneration. Conclusions Necrosome activation contributed to photodamage-induced rod and cone degeneration. The visual cycle and autophagy are the important therapeutic targets to alleviate light-induced retinal necroptosis.

Hyperoside mitigates photoreceptor degeneration in part by targeting cGAS and suppressing DNA-induced microglial activation

“…Release of non-histone nuclear protein HMGB1 signifies necrotic cell damage and ensuing inflammation [ 11 ]. This phenomenon has been noted in the light-damaged retinas [ 12 ]. Consistently, our previous study has also documented that degenerative photoreceptors (1 d and 3 d post illumination) are characterized by diminishment in the nuclear HMGB1 [ 13 ].…”