Tumor necrosis factor alpha has an early protective effect on retinal ganglion cells after optic nerve crush

摘要

Background 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. 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 TNF?. Despite strong evidence implicating this protein in neurodegeneration, a direct injection of TNF? does not mimic the rapid loss of RGCs observed after acute optic nerve trauma or exposure to excitotoxins. This suggests that our understanding of TNF? signaling is incomplete. Methods RGC death was induced by optic nerve crush in mice. The role of TNF? in this process was examined by quantitative PCR of Tnf? gene expression, and quantification of cell loss in Tnf??/? mice or in wild-type animals receiving an intraocular injection of exongenous TNF? either before or after crush. Signaling pathways downstream of TNF? were examined by immunolabeling for JUN protein accumulation or activation of EGFP expression in NF?B reporter mice. Results Optic nerve crush caused a modest increase in Tnf? gene expression, with kinetics similar to the activation of both macroglia and microglia. A pre-injection of TNF? attenuated ganglion cell loss after crush, while ganglion cell loss was more severe in Tnf??/? mice. Conversely, over the long term, a single exposure to TNF? induced extrinsic apoptosis in RGCs. Müller cells responded to exogenous TNF? by accumulating JUN and activating NF?B. Conclusion Early after optic nerve crush, TNF? appears to have a protective role for RGCs, which may be mediated through Müller cells.