title: Tumor necrosis factor alpha has an early protective effect on retinal ganglion cells after optic nerve crush.
abstract: 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 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.
  
  
  METHODS
  RGC 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.
  
  
  RESULTS
  Optic 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.
  
  
  CONCLUSIONS
  Early after optic nerve crush, TNFα appears to have a protective role for RGCs, which may be mediated through Müller cells.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, 571A MSC - 1300 University Ave., Madison, WI, 53706, USA. cemacnair@wisc.edu.|Cellular and Molecular Pathology Graduate Program, University of Wisconsin, 3170-10 K/L MFCB - 1685 Highland Ave., Madison, WI, 53705, USA. cemacnair@wisc.edu.
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: Mac Nair
authors.affiliation: Flaum Eye Institute, University of Rochester Medical Center, 601 Elmwood Ave., Box 659, Rochester, NY, 14642, USA. kfernandes@URMC.Rochester.edu.
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Fernandes
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, 571A MSC - 1300 University Ave., Madison, WI, 53706, USA. clschlamp@wisc.edu.
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Schlamp
authors.affiliation: Flaum Eye Institute, University of Rochester Medical Center, 601 Elmwood Ave., Box 659, Rochester, NY, 14642, USA. richard_libby@URMC.Rochester.edu.|Department of Biomedical Genetics, University of Rochester Medical Center, 601 Elmwood Ave., Box 633, Rochester, NY, 14642, USA. richard_libby@URMC.Rochester.edu.|The Center for Visual Sciences, University of Rochester Medical Center, 274 Meliora Hall, RC Box 270270, Rochester, NY, 14627, USA. richard_libby@URMC.Rochester.edu.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Libby
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Wisconsin, 571A MSC - 1300 University Ave., Madison, WI, 53706, USA. nickells@wisc.edu.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Nickells
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009409:Nerve Crush; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D020221:Optic Nerve Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D018696:Neuroprotective Agents; D014409:Tumor Necrosis Factor-alpha