Inflammation In Retinal Injury

Objective:Ischemia contributes to multiple ocular diseases, including glaucoma and diabetic retinopathy. Neuron loss, glial activation and vascular degeneration are common sequelae of ischemia and reperfusion (I/R) injury. Inflammation plays important roles in the development of diabetic retinopathy and I/R injury. Histone modifications are important epigenetic changes that play critical roles in gene regulation. We hypothesized that histone modifications lead to the inflammatory response in retinal I/R injury and diabetic retinopathy.Methods:Retinal ischemia was induced by high intraocular pressure and diabetes was induced by STZ (streptozotocin) injection. Western blotting, immunoflurensence, qPCR and ChIP assay were performed to identify the changes of inflammatory response, histone modification and cell death both in vivo and in vitro. Curcumin diets were used to treat I/R-induced retinal injury, and minocycline was used to treat the high glucose cultured rMC-1cells, a Muller cell line.Results:Pre-treatment with0.01%,0.05%or0.25%curcumin in diets significantly inhibited the I/R-induced ganglion cell loss.0.05%curcumin pre-treatment inhibited the I/R-induced degeneration of capillaries, apoptotic cell death in GCL, and β-tubulin Ⅲ downregulation, while this dosage showed no effect on the injury-induced GFAP overexpression.0.05%curcumin pre-treatment inhibited the I/R-induced induction of the inflammatory chemokine, MCP-1, as well as activation of NF-κB and STAT3, but had no effect on activation of ERK. Moreover,0.05%curcumin showed vascular protective effects even when administrated after neurodegeneration was extensive.In the retinas of diabetic rats, significantly elevated histone acetylations were found, accompanied with increased histone acetyltranferases levels and decreased histone deacetylases levels. Elevated AcH3K9and AcH3K18were partially co-stained with Muller cells on diabetic retinas. Consistently, high glucose (HG) treated rMC-1cells also showed up-regulation of acetylated histones, accompanied with the over-expression of GFAP, p-STAT3and NF-KB-p65, and two inflammatory genes, TNFα and MCP-1. Minocycline was found to down-regulate the HG-induced Muller cell activation, inflammation and acetylated H3K18bound to the promoters of GFAP and inflammatory genes.Conclusions:1) Curcumin showed neuro-and vaso-protective effects in the rat modle of retinal I/R injury. The beneficial effects of curcumin on neurovascular degeneration may be through its inhibitory effects on the injury-induced NF-kB activation, STAT3activation and MCP-1overexpression. Curcumin may therefore serve as a promising prodrug candidate for retinal ischemia diseases.2) Elevation of histone acetylations in Muller cells plays important regulating roles in the inflammation response during diabetic conditions. Inhibition of histone acetylation by minocycline is a novel function that may contribute to its beneficial effects on DR.