Abstract
BackgroundGlaucoma is an optic neuropathy that is characterized by the loss of retinal ganglion cells (RGCs) initiated by damage to axons in the optic nerve. The degeneration and death of RGCs has been thought to occur in two waves. The first is axogenic, caused by direct insult to the axon. The second is somatic, and is thought to be caused by the production of inflammatory cytokines from the activated retinal innate immune cells. One of the cytokines consistently linked to glaucoma and RGC damage has been TNFα. Despite strong evidence implicating this protein in neurodegeneration, a direct injection of TNFα does not mimic the rapid loss of RGCs observed after acute optic nerve trauma or exposure to excitotoxins. This suggests that our understanding of TNFα signaling is incomplete.MethodsRGC death was induced by optic nerve crush in mice. The role of TNFα in this process was examined by quantitative PCR of Tnfα gene expression, and quantification of cell loss in Tnfα−/− mice or in wild-type animals receiving an intraocular injection of exongenous TNFα either before or after crush. Signaling pathways downstream of TNFα were examined by immunolabeling for JUN protein accumulation or activation of EGFP expression in NFκB reporter mice.ResultsOptic nerve crush caused a modest increase in Tnfα gene expression, with kinetics similar to the activation of both macroglia and microglia. A pre-injection of TNFα attenuated ganglion cell loss after crush, while ganglion cell loss was more severe in Tnfα−/− mice. Conversely, over the long term, a single exposure to TNFα induced extrinsic apoptosis in RGCs. Müller cells responded to exogenous TNFα by accumulating JUN and activating NFκB.ConclusionEarly after optic nerve crush, TNFα appears to have a protective role for RGCs, which may be mediated through Müller cells.
Highlights
Glaucoma is an optic neuropathy that is characterized by the loss of retinal ganglion cells (RGCs) initiated by damage to axons in the optic nerve
While many inflammatory cytokines have been linked to RGC degeneration [21,32,33], tumor necrosis factor alpha (TNFα) has been consistently associated with glaucomatous neuropathy [10,11,23,34,35,36,37]
TNFα expression is stimulated following optic nerve crush injury An increase in Tnfα mRNA expression has been correlated with RGC and optic nerve injury; the time course of this expression to the best of our knowledge has not been documented
Summary
Glaucoma is an optic neuropathy that is characterized by the loss of retinal ganglion cells (RGCs) initiated by damage to axons in the optic nerve. Some research suggests that the innate immune response is critical for RGC protection after injury [21,22], while research in stroke and ischemia models demonstrate greater neuronal loss from activated glia [14,23,24] In the latter paradigm, glial activation is thought to cause a second wave of RGC loss, termed secondary degeneration [7,11,25]. It has been hypothesized that these cytokines are generated from either macroglia, principally Müller cells [28], or microglia [20], or both Supporting evidence for this model comes from studies showing that minocycline, a broad spectrum anti-inflammatory drug, protects RGCs against optic nerve axotomy, experimental glaucoma, and optic nerve crush [7,29,30,31], implicating a damaging role for the immune response after injury. While many inflammatory cytokines have been linked to RGC degeneration [21,32,33], TNFα has been consistently associated with glaucomatous neuropathy [10,11,23,34,35,36,37]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
