Recent studies on the endoplasmic reticulum stress have shown that the unfolded protein response (UPR) is involved in the pathogenesis of inherited
retinal degeneration caused by mutant
rhodopsin. However, the main question of whether UPR activation actually triggers
retinal degeneration remains to be addressed. Thus, in this study, we created a mouse model for
retinal degeneration caused by a persistently activated UPR to assess the physiological and morphological parameters associated with this disease state and to highlight a potential mechanism by which the UPR can promote
retinal degeneration. We performed an
intraocular injection in C57BL6 mice with a known unfolded protein response (UPR) inducer,
tunicamycin (Tn) and examined animals by electroretinography (ERG), spectral domain optical coherence tomography (SD-OCT) and histological analyses. We detected a significant loss of photoreceptor function (over 60%) and
retinal structure (35%) 30 days post treatment. Analysis of
retinal protein extracts demonstrated a significant upregulation of inflammatory markers including interleukin-1β (IL-1β),
IL-6,
tumor necrosis factor-α (TNF-α),
monocyte chemoattractant protein-1 (MCP-1) and IBA1. Similarly, we detected a strong inflammatory response in mice expressing either Ter349Glu or T17M
rhodopsin (RHO). These mutant
rhodopsin species induce severe
retinal degeneration and T17M
rhodopsin elicits UPR activation when expressed in mice.
RNA and
protein analysis revealed a significant upregulation of pro- and anti-inflammatory markers such as IL-1β,
IL-6, p65
nuclear factor kappa B (
NF-kB) and MCP-1, as well as activation of F4/80 and IBA1 microglial markers in both the retinas expressing mutant
rhodopsins. We then assessed if the Tn-induced inflammatory marker IL-1β was capable of inducing
retinal degeneration by injecting C57BL6 mice with a recombinant IL-1β. We observed ~19% reduction in ERG a-wave amplitudes and a 29% loss of photoreceptor cells compared with control retinas, suggesting a potential link between pro-inflammatory
cytokines and
retinal pathophysiological effects. 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
cytokine IL-1β.