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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 3

Hierarchical clustering identified early stages of glaucoma.

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Hierarchical clustering identified early stages of glaucoma.
(A) Glaucom...
(A) Glaucoma-relevant probe sets were used to cluster eyes based on similarity of ONH expression profiles. All eyes included in this study were at early stages, prior to optic nerve damage (see Methods). Four molecularly defined stages containing at least 5 DBA/2J eyes were identified (stages 1a, 1b, 1c, and 2; named for consistency with a previous study, ref. 26). Stages were ordered based on the increasing number of DE genes compared with those in the D2-Gpnmb+ control group (D2-Gp1) and based on the previous study, which also identified stage 2 and subsequent stages. Normalized intensity values for probe sets are represented as “green to black to red,” with green indicating lower normalized intensity values, and red indicating higher normalized intensity values. (B) A summary of the relationships among control groups, stages of glaucoma, and the radiation-treated group. The dendrogram shows that radiation-treated eyes (red) are most similar to eyes of stage 1b. In fact, 10 radiation-treated eyes clustered with the eyes in stage 1b (see A). This demonstrates that stresses and early molecular changes that occur in glaucoma persist in radiation-treated eyes, but the treatment prevents further progression. The sensitivity of this clustering approach is evident by the splitting of control eyes into 2 groups (D2-Gp1 and D2-Gp2, see Methods). (C) Pairwise comparisons between molecular groups and D2-Gp1. The sample number and the number of DE genes for each group are shown. Similar results were obtained when comparing glaucoma stages to D2-Gp2.

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

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