Patterns of NFkB activation resulting from damage, reactive microglia, cytokines, and growth factors in the mouse retina

Abstract

Muller 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 Muller glia into progenitor cells is key to reversing the loss of vision that occurs with retinal diseases. In the mammalian retina, NF{kappa}B signaling promotes glial reactivity and represses the reprogramming of Muller glia into progenitor cells. Here we investigate different cytokines, growth factors, cell signaling pathways, and damage paradigms that influence NF{kappa}B-signaling in the mouse retina. We find that exogenous TNF and IL1{beta} potently activate NF{kappa}B-signaling in Muller glia in undamaged retinas, and this activation is independent of microglia. By comparison, TLR1/2 agonist indirectly activates NF{kappa}B-signaling in Muller 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 NF{kappa}B-signaling, whereas CNTF, Osteopontin, WNT4, or inhibition of GSK3{beta} activated NF{kappa}B in Muller glia in the absence of neuronal damage. By comparison, dexamethasone, a glucocorticoid agonist, suppressed NF{kappa}B-signaling in Muller glia in damaged retinas, in addition to reducing numbers of dying cells and the accumulation of reactive microglia. Although NMDA-induced retinal damage activated NF{kappa}B in Muller glia, optic nerve crush had no effect on NF{kappa}B activation within the retina, whereas glial cells within the optic nerve were responsive. We conclude that the NF{kappa}B pathway is activated in retinal Muller glia in response to many different cell signaling pathways, and activation often depends on signals produced by reactive microglia.