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

被引:355
作者
Nakazawa, Toru
Nakazawa, Chifuyu
Matsubara, Akihisa
Noda, Kousuke
Hisatomi, Toshio
She, Haicheng
Michaud, Norman
Hafezi-Moghadam, Ali
Miller, Joan W.
Benowitz, Larry I.
机构
[1] Childrens Hosp, Dept Neurosurg, Boston, MA 02115 USA
[2] Childrens Hosp, Neurobiol Program, Boston, MA 02115 USA
[3] Massachusetts Eye & Ear Infirm, Angiogenesis Lab, Boston, MA 02114 USA
[4] Harvard Univ, Sch Med, Dept Ophthalmol, Boston, MA 02115 USA
[5] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA
[6] Harvard Univ, Sch Med, Program Neurosci, Boston, MA 02115 USA
关键词
glaucoma; retinal ganglion cell; optic nerve; cytokines; oligodendrocyte; microglia;
D O I
10.1523/JNEUROSCI.2801-06.2006
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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. Copyright © 2006 Society for Neuroscience.
引用
收藏
页码:12633 / 12641
页数:9
相关论文
共 58 条
  • [1] Microarray analysis of changes in mRNA levels in the rat retina after experimental elevation of intraocular pressure
    Ahmed, F
    Brown, KM
    Stephan, DA
    Morrison, JC
    Johnson, EC
    Tomarev, SI
    [J]. INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2004, 45 (04) : 1247 - 1258
  • [2] Experimental mouse ocular hypertension: Establishment of the model
    Aihara, M
    Lindsey, JD
    Weinreb, RN
    [J]. INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE, 2003, 44 (10) : 4314 - 4320
  • [3] Alldred A, 2001, Expert Opin Pharmacother, V2, P1137, DOI 10.1517/14656566.2.7.1137
  • [4] Microglial major histocompatibility complex glycoprotein-1 in the axotomized facial motor nucleus: Regulation and role of tumor necrosis factor receptors 1 and 2
    Bohatschek, M
    Kloss, CUA
    Hristova, M
    Pfeffer, K
    Raivich, G
    [J]. JOURNAL OF COMPARATIVE NEUROLOGY, 2004, 470 (04) : 382 - 399
  • [5] TUMOR-NECROSIS-FACTOR, ITS RECEPTORS AND THE CONNECTION WITH INTERLEUKIN-1 AND INTERLEUKIN-6
    BROUCKAERT, P
    LIBERT, C
    EVERAERDT, B
    TAKAHASHI, N
    CAUWELS, A
    FIERS, W
    [J]. IMMUNOBIOLOGY, 1993, 187 (3-5) : 317 - 329
  • [6] MORPHOLOGICAL-CHANGES IN OLIGODENDROCYTES IN THE INTACT MOUSE OPTIC-NERVE FOLLOWING INTRAVITREAL INJECTION OF TUMOR-NECROSIS-FACTOR
    BUTT, AM
    JENKINS, HG
    [J]. JOURNAL OF NEUROIMMUNOLOGY, 1994, 51 (01) : 27 - 33
  • [7] Distribution, markers, and functions of retinal microglia
    Chen, L
    Yang, PZ
    Kijlstra, A
    [J]. OCULAR IMMUNOLOGY AND INFLAMMATION, 2002, 10 (01) : 27 - 39
  • [8] Axon degeneration mechanisms: Commonality amid diversity
    Coleman, M
    [J]. NATURE REVIEWS NEUROSCIENCE, 2005, 6 (11) : 889 - 898
  • [9] Real-time imaging of single nerve cell apoptosis in retinal neurodegeneration
    Cordeiro, MF
    Guo, L
    Luong, V
    Harding, G
    Wang, W
    Jones, HE
    Moss, SE
    Sillito, AM
    Fitzke, FW
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (36) : 13352 - 13356
  • [10] Anti-TNF-alpha therapy in ankylosing spondylitis
    De Keyser, F
    Van den Bosch, F
    Mielants, H
    [J]. CYTOKINE, 2006, 33 (05) : 294 - 298