Voluntary exercise preserves visual function and reduces inflammatory cytokine expression in an adult mouse model of autosomal dominant retinitis pigmentosa

Abstract

Purpose : Exercise has been shown to be an effective rehabilitative intervention for retinal degenerative diseases. An important aspect of exercise-induced retinal protection is preventing neuroinflammation from accelerating disease onset and progression. In the present study, we investigate a neuroimmune mechanism underlying voluntary running wheel exercise in suppressing retinal inflammatory responses in a mouse model of class B1 autosomal dominant retinitis pigmentosa (adRP).

Methods : Brief exposure of C57BL/6J mice heterozygous for mutation I307N in rhodopsin (Rho; also known as RHO^Tvrm4/+) to bright light induces rod photoreceptor degeneration. Male and female I307N Rho mice (n=56) were given access to free spinning (active) or locked (inactive) running wheels. After two weeks, half of each cohort was exposed to bright light (6,000 lux; induced) for 5 min and returned to their wheels. At 1- and 2-weeks post-induction, electroretinograms (ERG) and optomotor response (OMR) were measured to assess retinal and visual function, respectively. After four weeks, mice were euthanized and eyes were collected for histological, Bio-Plex cytokine assay and immunohistochemistry analyses.

Results : Active induced mice had greater ERG amplitudes (scotopic a-wave: p=0.0005; scotopic b-wave: p=0.0034; photopic b-wave: p=0.0280) and OMR thresholds (spatial frequency: p<0.0001; contrast sensitivity: p<0.0001) compared to inactive induced mice. Active induced mice had greater numbers of photoreceptor nuclei compared to inactive induced mice (p=0.0031). Cytokine analysis of retinal extracts showed reductions of keratinocyte-derived chemokine (KC; p=0.018) and interferon gamma-induced protein 10 (IP-10; p=0.038) expression in active mice compared to inactive mice . Immunohistochemistry revealed KC and IP-10 expression was localized to retinal vasculature by co-labeling with vascular marker collagen IV.

Conclusions : Voluntary running wheel exercise preserved retinal and visual function and photoreceptor nuclei in an inducible mouse model of adRP. We also observed novel findings of suppressed KC and IP-10 expression in active induced mice, with expression localized to retinal vasculature. Overall, our findings highlight the potential role of retinal vascular derived chemokines in modulating retinal neuroinflammation during exercise.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.