Interleukin 27-induced photoreceptor survival is associated with suppression of a novel Muller glia subpopulation

Retinal degenerations are associated with aberrant activation of inflammation. Interleukin-27 (IL-27) is a cytokine with anti-inflammatory and neuroprotective activities in the CNS. However, the molecular and cellular mechanisms by which IL-27 mediates its neuroprotective effects remain unclear. The rd10 mouse model of retinal degeneration received an intravitreal injection of IL-27 or saline prior to degeneration. IL-27 induced sustained retina protection for at least four weeks after injection. SnRNA-seq analysis demonstrated suppression of a unique Muller glia subpopulation in IL-27 treated mice. Moreover, snRNA-seq revealed differential expression of distinct gene categories across glial and photoreceptor cell types, including genes involved in ATP synthesis, metabolism, protein translation, apoptosis, inflammation and extracellular matrix. Therefore, reducing reactive inflammation in early retinal disease with IL-27 leads to changes in numerous cellular pathways and sustained neuroprotection in rd10 mice. Additionally, our findings suggest that suppression of a specific Muller glia subpopulation contributes to the neuroprotective effect of IL-27. Therefore, this study identified new pathways of neuroprotection in the retina. 1) Intravitreal injection of the IL-27 cytokine in retinal degeneration 10 (rd10) mice early in disease leads to sustained photoreceptor protection for at least four weeks. 2) IL-27 - mediated photoreceptor protection is associated with suppression of a novel Muller glia subpopulation and alteration of extracellular matrix and metabolic pathways in glia. 3) These results demonstrate that IL-27 is a potent protective molecule that alters the inflammatory and glial characteristics of the retina to induce photoreceptor survival.