Tumor necrosis factor-alpha mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma.
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-alpha (TNF-alpha) 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-alpha, followed sequentially by microglial activation, loss of optic nerve oligodendrocytes, and delayed loss of RGCs. Intravitreal TNF-alpha injections in normal mice mimicked these effects. Conversely, an anti-TNF-alpha-neutralizing antibody or deleting the genes encoding TNF-alpha 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-alpha provides an essential, although indirect, link between OH and RGC loss in vivo. Blocking TNF-alpha signaling or inflammation, therefore, may be helpful in treating glaucoma.
Nakazawa
Toru
T
Angiogenesis Laboratory, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts 02114, USA.
Nakazawa
Chifuyu
C
Matsubara
Akihisa
A
Noda
Kousuke
K
Hisatomi
Toshio
T
She
Haicheng
H
Michaud
Norman
N
Hafezi-Moghadam
Ali
A
Miller
Joan W
JW
Benowitz
Larry I
LI
D000818:Animals; D002452:Cell Count; D016923:Cell Death / Q000502:physiology; D004195:Disease Models, Animal; D005901:Glaucoma / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009798:Ocular Hypertension / Q000209:etiology / Q000473:pathology; D009836:Oligodendroglia / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D012165:Retinal Ganglion Cells / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000502:physiology*
D014409:Tumor Necrosis Factor-alpha