Most forms of induced and inherited retinal degeneration involve induction of neuroinflammation that is characterized by changes in Müller glia and microglia, and at least some of these changes accelerate vision loss in advanced blinding diseases. The specific triggers, hierarchy of molecular steps, and cellular interactions that promote these changes initially are still largely obscure. However, it is generally thought that Müller glia and microglia activation is secondary to distress signals and cellular debris following programmed cell death of photoreceptor or other neurons in the retina. Here, we report early changes in gene and protein expression in acutely induced or inherited, chronic mouse and rat models of retinal degeneration. We identified patterns of cytokine communication originating in the outermost layer of the retina, the retinal pigment epithelium (RPE) through signaling via phagocytic receptors of the Tyro3/Axl/MERTK (TAM) family, and responses by Müller glia and microglia cells. Some of these changes occur early postnatally, at ages prior to full retinal maturity and visual function when there is no evidence of neural retina distress let alone neuronal death. Finally, we found that either reducing microglia activation pharmacologically or cytokine reduction through gene knockout was sufficient to lessen severity of neurodegeneration and delay vision loss. Targeted pharmacological interference with early inflammatory crosstalk of RPE, Müller glia and microglia, which precedes neuronal death, may be a therapeutic approach for blinding diseases that are yet without cure.