Etanercept, a Widely Used Inhibitor of Tumor Necrosis Factor-α (TNF- α), Prevents Retinal Ganglion Cell Loss in a Rat Model of Glaucoma

Miin Roh,Larry I Benowitz,Aristomenis Thanos,Sung Chul Lee,Yan Zhang,Joan W Miller,Demetrios G Vavvas,Yusuke Murakami,Steven Barnes

doi:10.1371/journal.pone.0040065

Abstract

BackgroundVisual loss in glaucoma is associated with pathological changes in retinal ganglion cell (RGC) axons and a slow decline in the RGC population. Age and elevated intraocular pressure (IOP) are the main risk factors for glaucomatous loss of vision. Several studies have implicated the proinflammatory cytokine tumor necrosis factor- α (TNF-α) as a link between elevated IOP and RGC death, but the cellular source of TNF-α and its causative role in RGC death remain uncertain. Here, using a rat model of glaucoma, we investigated the source of elevated TNF- α and examined whether Etanercept, a TNF-α blocker that is in common clinical use for other indications, is protective against RGC death.Methodology/Principal FindingsEpiscleral vein cauterization (EVC) caused intraocular pressure (IOP) to be elevated for at least 28 days. IOP elevation resulted in a dramatic increase in TNF-α levels within a few days, axonal degeneration, and a 38% loss of RGCs by 4 weeks. Immunostaining coupled with confocal microscopy showed that OHT induced robust induction of TNF-α in Iba-1-positive microglia around the optic nerve head (ONH). Despite persistent elevation of IOP, Etanercept reduced microglial activation, TNF-α levels, axon degeneration in the optic nerve, and the loss of RGCs.Conclusions/SignificanceOcular hypertension (OHT) triggers an inflammatory response characterized by the appearance of activated microglia around the ONH that express TNF-α. Blocking TNF-α activity with a clinically approved agent inhibits this microglial response and prevents axonal degeneration and loss of RGCs. These findings suggest a new treatment strategy for glaucoma using TNF- α antagonists or suppressors of inflammation.

Highlights

Retinal ganglion cell (RGC) death and subsequent visual field defects that progress to blindness are the underlying pathophysiology of glaucoma [1]
The current study confirms and extends previous findings linking retinal ganglion cell (RGC) loss in glaucoma to tumor necrosis factor- a (TNF-a). Our results demonstrate this link using a different method to induce ocular hypertension (OHT) and a different species than our earlier study, while for the first time identifying microglia at the optic nerve head (ONH) as the source of TNF-a
We elevated intraocular pressure (IOP) by episcleral vein cauterization (EVC), which led to axon degeneration in the optic nerve and eventual loss of RGCs

Summary

Introduction

Retinal ganglion cell (RGC) death and subsequent visual field defects that progress to blindness are the underlying pathophysiology of glaucoma [1]. Lowering IOP with surgery or drugs reduces the rate of optic nerve head (ONH) damage and progressive visual field loss by almost half, firmly establishing IOP reduction as an effective treatment for glaucoma. Proposed mechanisms linking RGC loss to elevated IOP include a compressive effect on the cribriform plates of the lamina cribrosa [5], pressure-induced tissue ischemia [6,7], and local cellular response mechanisms [8]. Age and elevated intraocular pressure (IOP) are the main risk factors for glaucomatous loss of vision. Several studies have implicated the proinflammatory cytokine tumor necrosis factor- a (TNF-a) as a link between elevated IOP and RGC death, but the cellular source of TNF-a and its causative role in RGC death remain uncertain. Using a rat model of glaucoma, we investigated the source of elevated TNF- a and examined whether Etanercept, a TNF-a blocker that is in common clinical use for other indications, is protective against RGC death

Methods

Results

Conclusion