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




Tumor necrosis factor alpha has an early protective effect on retinal ganglion cells after optic nerve crush - Download this document for free, or read online. Document in PDF available to download.

Journal of Neuroinflammation

, 11:194

First Online: 19 November 2014Received: 10 June 2014Accepted: 03 November 2014

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 NFkB.

ConclusionEarly after optic nerve crush, TNFα appears to have a protective role for RGCs, which may be mediated through Müller cells.

KeywordsSecondary degeneration Neuroinflammation TNFα Retinal ganglion cell Macroglia AbbreviationsCASPCaspase

DAPI4’,6-diamidino-2-phenylindole

EGFPenhanced green fluorescent protein

GCLganglion cell layer

PBSphosphate-buffered saline

PCRpolymerase chain reaction

qPCRquantitative polymerase chain reaction

RGCretinal ganglion cell

TNFαtumor necrosis factor alpha

TNFR1tumor necrosis factor alpha receptor 1

TNFR2tumor necrosis factor alpha receptor 2

Electronic supplementary materialThe online version of this article doi:10.1186-s12974-014-0194-3 contains supplementary material, which is available to authorized users.

Download fulltext PDF



Author: Caitlin E Mac Nair - Kimberly A Fernandes - Cassandra L Schlamp - Richard T Libby - Robert W Nickells

Source: https://link.springer.com/



DOWNLOAD PDF




Related documents