Molecular and cellular mechanisms of IL-27-induced neuroprotection in a mouse model of inherited retinal degeneration

Retinal degenerations are associated with aberrant activation of the innate immune system and broad acting anti-inflammatory agents partially reduce the amount of degeneration in animal models. Interleukin-27 (IL-27) is a cytokine in the IL-12 family that has anti-inflammatory activity in the CNS. We previously demonstrated in the rd10 mouse model of inherited retinal degeneration that an intravitreal injection of recombinant IL-27 provided photoreceptor protection and vision rescue for 2 weeks after injection. However, the molecular and cellular mechanisms by which IL-27 mediates its neuroprotective effects and the duration of protection are unknown. In this study, we tested the hypothesis that reducing inflammation at the early stages of degeneration prior to substantial photoreceptor loss would prolong vision rescue. Rd10 mice received an intravitreal injection of 20 ng IL-27 or saline prior to degeneration, and photoreceptor survival was measured 4 and 7 weeks later by optomotor assay, ERG, TUNEL and cone photoreceptor density. Early molecular changes were assessed by snRNAseq, cytoplex and immunohistochemistry. We demonstrated that IL-27 induced sustained retina protection compared to saline at 4 but not 7 weeks after injection. Additionally, snRNAseq analysis two days after injection demonstrated suppression of a unique Muller glia subpopulation in IL-27 treated mice and differential expression of distinct gene categories across glial and photoreceptor cell types, including genes involved in ATP synthesis, transcription and translation, apoptosis and extracellular matrix. Therefore, reducing reactive inflammation prior to the peak of photoreceptor degeneration using IL-27 leads to changes in numerous cellular pathways and sustained neuroprotection in rd10 mice. Additionally, these findings suggest that suppression of a reactive Muller glia subset and critical glial signaling pathways contribute to the neuroprotective effect of IL-27.