Nuclear Factor Kappab Is a Key Regulator of Glial Neurotoxicity in Retinal Pathologies

Abstract

Purpose: : In response to optic nerve and retinal injury astrocytes undergo reactivation, abandon normal supportive and acquire pro-inflammatory functions. These changes contribute to neuroinflammation, oxidative stress and facilitate loss of retinal ganglion cells (RGCs). Here we sought to examine the effect of targeted suppression of a key pro-inflammatory/stress-response transcription factor NF-ΚB in astrocytes on the survival of RGCs exposed to various insults.

Methods: : We utilized transgenic (TG) mice with astrocyte-specific suppression of NF-ΚB through GFAP promoter-controlled inhibition of p65/p50 translocation. We have tested the effects of astrocytic NF-kB suppression in several disease models, including acute ischemia, optic neuritis and chronic ocular hypertension, characterized by considerable astrocyte reactivation.

Results: : All disease models showed significantly higher residual neuronal density in ganglion cell layers of TG vs. wild type (WT) retinas, an evidence of RGC protection via inhibition of astroglial NF-kB. The analysis of gene expression revealed relative suppression of pro-inflammatory and ROS-producing pathways, and activation of pro-survival, anti-inflammatory ones in TG vs. WT retinas and optic nerves in all models. In particular, we detected downregulation of pro-inflammatory Tnfa, IL1b and activation of anti-inflammatory Tgfb1, Stat3, Fractalkine/Cx3cl1 genes among the others. Immunohistochemistry confirmed differential activation of key genes in these pathways. In vitro experiments with purified primary astrocytes and retinal ganglion cells confirmed causative relationship between reactive NF-kB activation in reactive astrocyte and neurotoxicity.

Conclusions: : Our data indicate that astrocytes play an active role in degeneration of neurons exposed to cytokines and injury. Our analysis implies that activated astrocytes facilitate RGC loss in various pathologies in the NF-kB-dependent manner. Inhibiting NF-ΚB in astrocytes results in neuroprotection, reduced inflammation and oxidative stress suggesting therapeutic potential y of astrocyte-targeting therapy in various ocular pathologies.

Keywords: astrocyte • inflammation • oxidation/oxidative or free radical damage