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S. A. Hussong, S. M. Kavanaugh, H. Roehrich, R. J. Kapphahn, D. A. Ferrington; An Alternate Role for Immunoproteasome in Retinal Stress Response. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3432.
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© ARVO (1962-2015); The Authors (2016-present)
The immunoproteasome is a proteasome subtype that produces antigenic peptides for MHC class I presentation and is an essential component of immune surveillance. This well-established role is inconsistent with immunoproteasome’s high content under normal conditions and upregulation with disease and injury in the immune-privileged retina (Ethen et al., FEBS Let 2007; Ferrington et al., J Neurochem 2008). The hypothesis is that immunoproteasome has an additional novel role in maintaining normal retinal homeostasis and in responding to retinal injury. To directly test this hypothesis, this study examines the retinal response to chronic (aging) and acute (light) stress with immunoproteasome deficiency.
Immunoproteasome-deficient mice (lmp7-/-mecl-1-/- (L7M1)) were used to investigate the importance of immunoproteasome in coping with retinal stress. The response of the L7M1 mouse retina to the chronic stress of aging and acute stress of constant light was evaluated from changes in protein expression, retinal morphology, and levels of apoptosis.
The basal level of apoptosis of photoreceptor nuclei increased with age in both WT and L7M1 (p<0.001). However, apoptosis was consistently higher in the L7M1 mice (p<0.001). These results correlated with a decrease in the number of photoreceptor nuclei with age in both L7M1 and WT (p<0.001) and consistently fewer nuclei in L7M1 mice at all ages (p<0.001). Proteomic analysis revealed significant changes in content of several redox-sensitive proteins and chaperones suggesting increased oxidative stress in L7M1 retina. These changes correlated with an increase in retinal protein oxidative modifications (p<0.001). Under constant light stress, immunoproteasome was upregulated in WT retina. While an increase in the level of apoptosis of photoreceptor nuclei was observed with constant light stress in both WT and L7M1 (p<0.001), apoptosis was consistently higher in the L7M1 mice (p<0.001).
These data support the hypothesis that the immunoproteasome performs functions that are essential for maintaining the overall retinal integrity with the chronic stress of aging and acute stress of constant light.
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