Elevating Jak-STAT signaling via SOCS3 deletion sustains photoreceptor viability and visual function in mouse models of retinitis pigmentosa.

Retinitis pigmentosa (RP) is an inherited retinal disease in which the loss of rod photoreceptors precedes cone photoreceptor degeneration. The neurocytokine ciliary neurotrophic factor (CNTF) can provide potent neuroprotection for photoreceptors in various retinal degeneration models and has thus been tested in clinical trials aimed at treating blinding diseases. In a preclinical model of RP, exogenous CNTF signaling mediated by the cytokine receptor gp130 initially triggered STAT3 and ERK phosphorylation in Muller glial cells and subsequently activated STAT3 in rods to promote photoreceptor survival. However, despite enhancing photoreceptor viability, the constitutive expression of exogenous CNTF perturbs the retinal transcriptome and further suppresses visual function. Activated STAT3 upregulates suppressor of cytokine signaling 3 (SOCS3), which acts as a feedback inhibitor to dampen cytokine signaling. In this study, we investigated whether eliminating SOCS3 in rod cells is sufficient to increase endogenous STAT3 signaling and enhance photoreceptor viability without exogenous CNTF. We show that rod-specific SOCS3 deletion attenuates photoreceptor degeneration and improves cone cell morphology in both the Pde6b/rd10 and Prph2(P216L)/rds mouse models of RP. SOCS3 ablation in rods not only causes STAT3 activation in rod photoreceptors but also leads to the propagation of STAT3 and ERK signaling to inner retinal cell types. Furthermore, rod SOCS3 deficiency led to improved visual function in the Pde6b/rd10 model and sustained cone function in the Prph2(P216L)/rds retina. Together, these findings demonstrate that intercellular communication occurs among retinal cells and the modulation of endogenous cytokine signaling events can be leveraged as an efficacious treatment to attenuate neuronal loss and preserve visual function.