Abstract
Müller glia are a cellular source for neuronal regeneration in vertebrate retinas. However, the capacity for retinal regeneration varies widely across species. Understanding the mechanisms that regulate the reprogramming of Müller glia into progenitor cells is key to reversing the loss of vision that occurs with retinal diseases. In the mammalian retina, NFkB signaling promotes glial reactivity and represses the reprogramming of Müller glia into progenitor cells. Here we investigate different cytokines, growth factors, cell signaling pathways, and damage paradigms that influence NFkB-signaling in the mouse retina. We find that exogenous TNF and IL1β potently activate NFkB-signaling in Müller glia in undamaged retinas, and this activation is independent of microglia. By comparison, TLR1/2 agonist indirectly activates NFkB-signaling in Müller glia, and this activation depends on the presence of microglia as Tlr2 is predominantly expressed by microglia, but not other types of retinal cells. Exogenous FGF2 did not activate NFkB-signaling, whereas CNTF, Osteopontin, WNT4, or inhibition of GSK3β activated NFkB in Müller glia in the absence of neuronal damage. By comparison, dexamethasone, a glucocorticoid agonist, suppressed NFkB-signaling in Müller glia in damaged retinas, in addition to reducing numbers of dying cells and the accumulation of reactive microglia. Although NMDA-induced retinal damage activated NFkB in Müller glia, optic nerve crush had no effect on NFkB activation within the retina, whereas glial cells within the optic nerve were responsive. We conclude that the NFkB pathway is activated in retinal Müller glia in response to many different cell signaling pathways, and activation often depends on signals produced by reactive microglia.