Role of tumor necrosis factor receptor-1 in the death of retinal ganglion cells following optic nerve crush injury in mice.
To assess the specific role of tumor necrosis factor (TNF) death receptor signaling in the induction of retinal ganglion cell (RGC) death, optic nerves of mice deficient for TNF receptor-1 (TNF-R1-/-) and control mice (C57BL/6J) were unilaterally subjected to crush injury. Counts of RGCs and their axons 6 weeks after the injury demonstrated that their loss was significantly less in TNF-R1-/- mice compared to controls. The most prominent decrease in neuronal loss detected in TNF-R1-/- mice was beyond the initial 2-week period after the injury. This time period was correlated with the period of glial activation and increased glial immunolabeling for TNF-alpha in these eyes. No further protection against neuronal loss was detectable in TNF-R1-/- mice treated with D-JNKI1, a specific inhibitor of c-Jun N-terminal protein kinase (JNK). However, anti-JNK treatment of control animals provided a significant protection against neuronal loss during the same secondary degeneration period. Phospho-JNK immunolabeling of RGCs in control mice subjected to optic nerve crush significantly decreased following their treatment with D-JNKI1, and anti-JNK treatment protected RGCs from degeneration in these animals, similar to the lack of TNF-R1. These findings provide evidence that TNF death receptor signaling is involved in the secondary degeneration of RGCs following optic nerve injury, and is associated with JNK signaling. Since secondarily degenerating neurons are viable targets for neuroprotection, inhibition of TNF death receptor signaling may be an effective strategy to protect RGCs in several neurodegenerative injuries.
Tezel
Gülgün
G
Department of Ophthalmology and Visual Sciences, University of Louisville School of Medicine, 301 E. Muhammad Ali Boulevard, Louisville, KY 40202, USA. gulgun.tezel@louisville.edu
Yang
Xiangjun
X
Yang
Junjie
J
Wax
Martin B
MB
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D008854:Microscopy, Electron; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009409:Nerve Crush; D009410:Nerve Degeneration / Q000378:metabolism; D009457:Neuroglia / Q000502:physiology; D020221:Optic Nerve Injuries / Q000473:pathology*; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology* / Q000648:ultrastructure; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D015703:Antigens, CD; D004791:Enzyme Inhibitors; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases