The unanticipated contribution of Zap70 in retinal degeneration: Implications for microglial inflammatory activation

Inflammation is a major mechanism of photoreceptor cell death in the retina during macular degeneration leading to the blindness. In this study, we investigated the role of the kinase molecule Zap70, which is an inflammatory regulator of the systemic immune system, to elucidate the control mechanism of inflammation in the retina. We observed activated microglial cells migrated and populated the retinal layer following blue LED-induced photoreceptor degeneration and activated microglial cells in the LED-injured retina expressed Zap70, unlike the inactive microglial cells in the normal retina. Visual function was considerably decreased in blue-LED light-exposed mice, and animals with Zap70 mutations were adversely affected. Furthermore, extensive photoreceptor cell death was observed in the SKG mice, bearing a Zap70 mutation that induces autoimmune disease. In the blue-LED light-exposed groups, SKG retinas had significantly higher levels of inflammatory cytokines than those in wild-type mice. Furthermore, regulating Zap70 activity has a significant influence on microglial inflammatory state. We discovered that active microglial cells expressing Zap70 could modify vascular endothelial growth factor A (Vegfa) signaling in primary retinal pigment epithelial (RPE) cells. Our novel study revealed that the production of Zap70 by retinal microglial cells is responsible for inflammatory signals that promote apoptosis in photoreceptor cells. Furthermore, Zap70-positive microglial cells were capable of regulating Vegfa signaling in RPE cells, which matches the hallmark of macular degeneration. Overall, we discovered Zap70's inflammatory activity in the retina, which is necessary for upregulating multiple inflammatory cytokines and cell death. Zap70 represents a novel therapeutic target for treating retinal degeneration.