Dysregulated inflammation contributes to retinal degeneration. Although inflammatory cells may initially
limit retinal damage by phagocytosing dying mutant photoreceptors and secreting reparative molecules,
excessive inflammation causes recruitment of additional reactive microglia, phagocytosis of viable
photoreceptors and toxic cytokine release, which accelerates retinal degeneration irrespective of the
primary mutation. Therefore, a central challenge for developing anti-inflammatory therapies for retinal
degenerations is to selectively suppress detrimental inflammation while maintaining beneficial
inflammatory responses. We recently demonstrated that the cytokine IL-27 regulates beneficial and
detrimental inflammatory signals in the retina and protects photoreceptors. IL-27 is a pleiotropic
cytokine that regulates tissue reactions to infection, neuronal disease and tumors. We found that higher
endogenous IL-27 levels were associated with photoreceptor protection induced by an innate immunity
inhibitor in the rd10 mouse model of inherited retinal degeneration. In studies directly testing IL-27
function, we demonstrated that intravitreal injections of IL-27 into rd10 led to reduced pro-inflammatory
cytokines, increased rod and cone photoreceptor survival and prolonged improvement in visual acuity.
Additionally, IL-27 increased markers of protective microglia and reduced neurotoxic microglia.
Because most research to date has focused on pro-inflammatory signals in the retina, a major
unanswered question is how anti-inflammatory regulators such as IL-27 reduce neurotoxic inflammation
during retinal degeneration. This proposed study will build upon our exciting data by defining
mechanisms by which IL-27 signaling regulates inflammation and promotes photoreceptor survival (Aim
1). Additionally, IL-27 is expressed in Muller glia and IL-27 receptors are in microglia but whether these
cells coordinate to regulate inflammation through IL-27 is not known. We will use conditional knockout
mice and gene overexpression to identify whether a novel Muller glia and microglia cytokine-cytokine
receptor signaling axis mediates IL-27-induced photoreceptor protection (Aim 2). The research team
combines the expertise of the PI, Abigail Hackam – retinal degeneration and neuroinflammation, and
collaborator Stefan Kurtenbach – scRNA seq and transcriptomics. The findings from this study will be
significant to identifying a novel regulatory signal that controls inflammation, which will be relevant for
precisely controlling inflammation and restoring tissue homeostasis during retinal degeneration. We will
also generate novel insights into the roles of Muller glia-microglia interactions in controlling retinal
inflammation. Finally, by characterizing a potential new therapeutic approach that is not dependent on
the primary mutation, this study will set the foundation for developing IL-27 as a therapeutic strategy for
protecting photoreceptors and rescuing vision during retinal disease.