Tumor necrosis factor-α mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma

Toru Nakazawa, Chifuyu Nakazawa, Akihisa Matsubara, Kousuke Noda, Toshio Hisatomi, Haicheng She, Norman Michaud, Ali Hafezi-Moghadam, Joan W. Miller, Larry I. Benowitz

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287 Citations (Scopus)

Abstract

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-α(TNF-α) 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-α, followed sequentially by microglial activation, loss of optic nerve oligodendrocytes, and delayed loss of RGCs. Intravitreal TNF-α injections in normal mice mimicked these effects. Conversely, an anti-TNF-α-neutralizing antibody or deleting the genes encoding TNF-αor 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-α provides an essential, although indirect, link between OH and RGCloss in vivo. Blocking TNF-α signaling or inflammation, therefore,may be helpful in treating glaucoma.

Original languageEnglish
Pages (from-to)12633-12641
Number of pages9
JournalJournal of Neuroscience
Volume26
Issue number49
DOIs
Publication statusPublished - 2006 Dec 6

Keywords

  • Cytokines
  • Glaucoma
  • Microglia
  • Oligodendrocyte
  • Optic nerve
  • Retinal ganglion cell

ASJC Scopus subject areas

  • Neuroscience(all)

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    Nakazawa, T., Nakazawa, C., Matsubara, A., Noda, K., Hisatomi, T., She, H., Michaud, N., Hafezi-Moghadam, A., Miller, J. W., & Benowitz, L. I. (2006). Tumor necrosis factor-α mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma. Journal of Neuroscience, 26(49), 12633-12641. https://doi.org/10.1523/JNEUROSCI.2801-06.2006