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The Journal of Neuroscience, December 6, 2006, 26(49):12633-12641; doi:10.1523/JNEUROSCI.2801-06.2006

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

Toru Nakazawa,^1,2,3,4 Chifuyu Nakazawa,^1,3 Akihisa Matsubara,^1,3 Kousuke Noda,^1,3 Toshio Hisatomi,^1,3 Haicheng She,^1,3 Norman Michaud,^1,3 Ali Hafezi-Moghadam,^1,3 Joan W. Miller,^1,3 and Larry I. Benowitz^2,4

¹Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, ²Department of Neurosurgery and Neurobiology Program, Children's Hospital Boston, Boston, Massachusetts 02115, and Departments of ³Ophthalmology and ⁴Surgery and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115

Correspondence should be addressed to either of the following: Dr. Larry Benowitz, Department of Neurosurgery and Neurobiology Program, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, Email: larry.benowitz{at}childrens.harvard.edu; or Dr. Joan W. Miller, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, 243 Cambridge Street, Boston, MA 02114, Email: Joan_Miller{at}meei.harvard.edu

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.

Key words: glaucoma; retinal ganglion cell; optic nerve; cytokines; oligodendrocyte; microglia

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Received June 30, 2006; revised Sept. 18, 2006; accepted Oct. 22, 2006.

Correspondence should be addressed to either of the following: Dr. Larry Benowitz, Department of Neurosurgery and Neurobiology Program, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, Email: larry.benowitz{at}childrens.harvard.edu; or Dr. Joan W. Miller, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, 243 Cambridge Street, Boston, MA 02114, Email: Joan_Miller{at}meei.harvard.edu

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