An Activated Unfolded Protein Response Triggers Retinal Degeneration in the Wild Type Mice Via Activation of Inflammatory Response.

Abstract

Purpose: Recently it has been shown that the UPR is involved in the pathogenesis of many retinal degenerative diseases. However, the main question of whether UPR activation actually triggers retinal degeneration remains to be addressed. The goal of this study is to verify the role of persistently activated UPR in retinal pathogenesis.<br />

Methods: C57BL6, T1117M Rho (ClassI) and Ter349Glu (ClassII) mice were used in the study. A mouse model of retinal degeneration caused by an activated UPR was created by injecting the C57BL6 mice with tunicamycin. ERG, SD-OCT and histological analysis were used to assess the physiological and morphological parameters associated with this disease. A potential mechanism by which the UPR triggers the retinal degeneration was delineated using the retinal RNA and protein extracts. <br />

Results: We detected a significant loss of wild type photoreceptor function (over 60%) and retinal structure (35%) 30 days post treatment. Analysis of retinal protein extracts demonstrated significant up-regulation of inflammatory markers IL-1β, IL-6, TNFα, MCP-1 and IBA1. Similar up-regulation of pro- and anti-inflammatory markers was found in the T17M RHO mice experiencing the UPR activation. The UPR activation was also found in other model of severe retinopathy expressing the Ter349Glu Rhodopsin though a protein misfolding is not a primary cause for UPR activation in this model. Interestingly, both mouse models demonstrated the activation of F4/80 and IBA1 microglial markers suggesting a link between the UPR activation and the inflammatory signaling. We then verified this link by testing a hypothesis of whether the early UPR-mediated IL-1β could be responsible for promotion of retinal degeneration. Approximately 19% reduction in the scotopic ERG a-wave amplitudes and a 29% loss of photoreceptor cells compared to control retinas were observed in the C57BL6 mice subretinaly injected with recombinant IL-1b, suggesting a potential link between pro-inflammatory cytokines and retinal pathophysiological effects.<br />

Conclusions: Our work demonstrates that in the context of an established animal model for ocular disease, the persistent activation of the UPR could be responsible for promoting retinal degeneration via the UPR-induced pro-inflammatory response.<br />