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Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma
Gareth R. Howell, … , Richard T. Libby, Simon W.M. John
Gareth R. Howell, … , Richard T. Libby, Simon W.M. John
Published March 19, 2012
Citation Information: J Clin Invest. 2012;122(4):1246-1261. https://doi.org/10.1172/JCI61135.
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Research Article Neuroscience Article has an altmetric score of 3

Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma

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Abstract

Glaucoma is a common ocular disorder that is a leading cause of blindness worldwide. It is characterized by the dysfunction and loss of retinal ganglion cells (RGCs). Although many studies have implicated various molecules in glaucoma, no mechanism has been shown to be responsible for the earliest detectable damage to RGCs and their axons in the optic nerve. Here, we show that the leukocyte transendothelial migration pathway is activated in the optic nerve head at the earliest stages of disease in an inherited mouse model of glaucoma. This resulted in proinflammatory monocytes entering the optic nerve prior to detectable neuronal damage. A 1-time x-ray treatment prevented monocyte entry and subsequent glaucomatous damage. A single x-ray treatment of an individual eye in young mice provided that eye with long-term protection from glaucoma but had no effect on the contralateral eye. Localized radiation treatment prevented detectable neuronal damage and dysfunction in treated eyes, despite the continued presence of other glaucomatous stresses and signaling pathways. Injection of endothelin-2, a damaging mediator produced by the monocytes, into irradiated eyes, combined with the other glaucomatous stresses, restored neural damage with a topography characteristic of glaucoma. Together, these data support a model of glaucomatous damage involving monocyte entry into the optic nerve.

Authors

Gareth R. Howell, Ileana Soto, Xianjun Zhu, Margaret Ryan, Danilo G. Macalinao, Gregory L. Sousa, Lura B. Caddle, Katharine H. MacNicoll, Jessica M. Barbay, Vittorio Porciatti, Michael G. Anderson, Richard S. Smith, Abbot F. Clark, Richard T. Libby, Simon W.M. John

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Figure 9

Restoring EDN2 to radiation-treated eyes induces a pattern of damage that is characteristic of glaucoma.

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Restoring EDN2 to radiation-treated eyes induces a pattern of damage tha...
EDN2, injected into the vitreous of radiation-treated eyes, caused glaucoma-like RGC damage that was not observed in control eyes. (A) Most radiation-treated, EDN2-injected DBA/2J eyes had moderate and severe optic nerve damage. This was not the case for EDN2-injected untreated D2-Gp or radiation-treated D2-Gp eyes or eyes injected with vehicle (1× PBS, n > 15 each group, all age matched). D2-Gp mice do not develop high IOP and glaucoma, and so EDN2 induces the most damage in eyes that have high IOP and possibly other stresses that are not sufficient by themselves to induce glaucoma. Thus, EDN2 is a damaging factor that conspires with other stresses to induce glaucoma but is diminished in radiation-treated eyes. (B) Axon counts demonstrated a significant increase in axon loss in radiation-treated, EDN2-injected DBA/2J eyes compared with that in D2-Gpnmb+ controls (*P < 0.0001). (C) Radiation-treated, EDN2-injected DBA/2J eyes had fan-shaped patterns of RGC loss, with discrete borders in the retina and regional axon loss in the ONHs (key characteristics of glaucoma). NFL, Anti-neurofilament antibody. Fan-shaped patterns were not observed in D2-Gpnmb+ or radiation-treated D2-Gpnmb+ controls. V, vessel. Scale bars: 100 μm (retina); 50 μm (ONH).

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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