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.