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

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          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-α 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-α provides an essential, although indirect, link between OH and RGC loss in vivo. Blocking TNF-α signaling or inflammation, therefore, may be helpful in treating glaucoma.

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          Author and article information

          Journal
          J Neurosci
          J. Neurosci
          jneurosci
          J. Neurosci
          The Journal of Neuroscience
          Society for Neuroscience
          0270-6474
          1529-2401
          6 December 2006
          : 26
          : 49
          : 12633-12641
          Affiliations
          [1] 1Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114,
          [2] 2Department of Neurosurgery and Neurobiology Program, Children's Hospital Boston, Boston, Massachusetts 02115, and
          [3]Departments of 3Ophthalmology and
          [4] 4Surgery and Program in Neuroscience, Harvard Medical School, Boston, Massachusetts 02115
          Author notes
          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, larry.benowitz@ 123456childrens.harvard.edu ; or Dr. Joan W. Miller, Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, 243 Cambridge Street, Boston, MA 02114, Joan_Miller@ 123456meei.harvard.edu

          T. Nakazawa's present address: Department of Ophthalmology, Tohoku University School of Medicine, Aoba-ku, Sendai 980-8575, Japan.

          Article
          PMC6674838 PMC6674838 6674838 3169084
          10.1523/JNEUROSCI.2801-06.2006
          6674838
          17151265
          ff81f345-2614-4cb3-8b82-0d41ea9c2924
          Copyright © 2006 Society for Neuroscience 0270-6474/06/2612633-09$15.00/0
          History
          : 30 June 2006
          : 18 September 2006
          : 22 October 2006
          Categories
          Articles
          Neurobiology of Disease
          Custom metadata

          microglia,oligodendrocyte,cytokines,optic nerve,retinal ganglion cell,glaucoma

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