TNF-α-Induced Optic Nerve Degeneration and Nuclear Factor-κB p65

Kitaoka, Yasushi; Kitaoka, Yuka; Kwong, Jessica Y. Y.; Ross‐Cisneros, Fred N.; Wang, Jiantao; Tsai, Rong‐Kung; Sadun, Alfredo A.; Lam, Tsun Ip

doi:10.1167/iovs.05-0299

Cited by 120 publications

(113 citation statements)

References 39 publications

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“…Previous studies have shown that intravitreal TNF-␣ injections lead to morphological changes in mouse oligodendrocytes (Butt and Jenkins, 1994) and that the loss of oligodendrocytes in the optic nerve affects the susceptibility of axons to excitotoxicity (Coleman, 2005;Stys, 2005). In addition, TNF-␣ has been shown to cause axonal loss and subsequent death of RGCs in rats (Kitaoka et al, 2006). Axonal damage resulting from nerve injury has been shown in many studies to induce a delayed loss of RGC somata (Nakazawa et al, 2002a).…”

Section: Discussionmentioning

confidence: 99%

“…In vivo, exogenous TNF-␣ prevents RGC death after optic nerve damage (Diem et al, 2001), although other studies show that it can cause the loss of RGC axons and a delayed loss of somata (Kitaoka et al, 2006). As yet, there is no direct evidence that TNF-␣ contributes to RGC death in glaucoma, nor is there any mechanistic understanding of how this might occur.…”

Section: Introductionmentioning

confidence: 99%

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Tumor Necrosis Factor-α Mediates Oligodendrocyte Death and Delayed Retinal Ganglion Cell Loss in a Mouse Model of Glaucoma

Nakazawa¹,

et al. 2006

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Glaucoma is a widespread ocular disease characterized by a progressive loss of retinal ganglion cells (RGCs). Previous studies suggest that the cytokine tumor necrosis factor-␣ (TNF-␣) may contribute to the disease process, although its role in vivo and its mechanism of action are unclear. To investigate pathophysiological mechanisms in glaucoma, we induced ocular hypertension (OH) in mice by angle closure via laser irradiation. This treatment resulted in a rapid upregulation of TNF-␣, followed sequentially by microglial activation, loss of optic nerve oligodendrocytes, and delayed loss of RGCs. Intravitreal TNF-␣ injections in normal mice mimicked these effects. Conversely, an anti-TNF-␣-neutralizing antibody or deleting the genes encoding TNF-␣ or its receptor, TNFR2, blocked the deleterious effects of OH. Deleting the CD11b/CD18 gene prevented microglial activation and also blocked the pathophysiological effects of OH. Thus TNF-␣ provides an essential, although indirect, link between OH and RGC loss in vivo. Blocking TNF-␣ signaling or inflammation, therefore, may be helpful in treating glaucoma.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tumor Necrosis Factor-α Mediates Oligodendrocyte Death and Delayed Retinal Ganglion Cell Loss in a Mouse Model of Glaucoma

Nakazawa¹,

et al. 2006

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“…Moreover, RGCs were significantly spared from degeneration in the STAT3-KO mice (Lupien et al, 2010). NFκB is a transcription factor expressed in neuronal and glial cells (Kitaoka et al, 2006) that regulates the expression of genes involved in inflammation, cell survival and apoptosis (Hayden & Ghosh, 2004). NFκB is multi-talented, able to upregulate anti-apoptotic factors but also activate pro-apoptotic pathways.…”

Section: Intracellular Pathwaysmentioning

confidence: 99%

Manipulating Glia to Protect Retinal Ganglion Cells in Glaucoma

Inman¹,

Lupien²,

Horner³

2011

Glaucoma - Current Clinical and Research Aspects

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“…We and other groups also demonstrated that intravitreal injection of TNF induces progressive optic nerve degeneration with slow RGC body death in mice 22 and rats. 23 These observations suggest that the TNF-induced neurodegeneration model may be useful in understanding the mechanism of axonal degeneration of the RGCs.…”

mentioning

confidence: 94%

Axonal Protection via Modulation of the Amyloidogenic Pathway in Tumor Necrosis Factor–Induced Optic Neuropathy

Kojima

Kitaoka²,

Munemasa³

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.To examine the changes in and localization of phosphorylated presenilin1 (p-PS1) and amyloid precursor protein (APP) in the optic nerve after intravitreal injection of TNF and to investigate the role of c-secretase in the cleavage of APP in optic nerve degeneration.METHODS. Groups of rats were euthanatized at 1 or 2 weeks after intravitreal injection of TNF. Levels of p-PS1 protein in the optic nerve were determined by immunoblotting and immunohistochemistry. The localization of APP was determined by immunohistochemistry, and its downstream cleavage was determined by immunoprecipitation using 6E10 antibody followed by immunoblotting with an APP intracellular domain (AICD) antibody. The effect of a c-secretase inhibitor on TNFinduced optic nerve degeneration was determined by counting the number of axons.RESULTS. p-PS1 was increased in the optic nerve after TNF injection and was found to colocalize with vimentin and glial fibrillary acidic protein, markers of astrocytes. Immunoprecipitation using 6E10 antibody followed by immunoblotting with AICD antibody revealed an increase in c-secretase activation in the optic nerve after TNF injection, which was inhibited by treatment with the c-secretase inhibitor. Moreover, c-secretase inhibition significantly prevented the loss of axons in the optic nerve after TNF injection.CONCLUSIONS. The increase in p-PS1 and activation of c-secretase in the optic nerve may be associated with TNF-induced axonal degeneration. Modulation of c-secretase activity may be useful for the treatment of TNF-related optic neuropathy. (Invest Ophthalmol Vis Sci. 2012;53:7675-7683)

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TNF-α-Induced Optic Nerve Degeneration and Nuclear Factor-κB p65

Abstract: TNF-alpha causes axonal degeneration with probable delayed loss of retinal ganglion cell bodies. NF-kappaB p65 may play a pivotal role in axonal degeneration, with the possible involvement of microglial cells.

Cited by 120 publications

References 39 publications

Tumor Necrosis Factor-α Mediates Oligodendrocyte Death and Delayed Retinal Ganglion Cell Loss in a Mouse Model of Glaucoma

Tumor Necrosis Factor-α Mediates Oligodendrocyte Death and Delayed Retinal Ganglion Cell Loss in a Mouse Model of Glaucoma

Manipulating Glia to Protect Retinal Ganglion Cells in Glaucoma

Axonal Protection via Modulation of the Amyloidogenic Pathway in Tumor Necrosis Factor–Induced Optic Neuropathy

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