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.
View: Text | PDF
Research Article Neuroscience

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

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

×

Figure 1

Sublethal γ-radiation protects DBA/2J mice from glaucoma.

Options: View larger image (or click on image) Download as PowerPoint
Sublethal γ-radiation protects DBA/2J mice from glaucoma. (A) Different ...
(A) Different doses of radiation protect from glaucoma. Most 18- to 21-month-old treated mice had no detectable optic nerve damage (NOE, n = 27). Doses of 7.5 Gy (n = 60, 12 months of age) and 5.0 Gy (n = 41) were highly protective compared to no treatment (0 Gy, n = 140) and equivalent to 10 Gy plus BMT (n = 54). 2.5 Gy (n = 35) was not protective. (B–D) ONHs of DBA/2J-Thy1(CFP) and irradiated DBA/2J-Thy1(CFP) 10-month-old mice were assessed for dystrophic neurites (big arrow) and axonal swellings (little arrow) by confocal microscopy. (B) Upper panels show compressed Z stacks of DBA/2J and Rad-D2 eyes imaging from the nerve fiber layer through the glial lamina. (C) Dystophic neurites and (D) axonal swellings were greatly reduced in irradiated compared to untreated eyes (n = 6 per group). (E and F) In the majority of 10-month-old Rad-D2 eyes (18/20), anterograde axon transport to the superior colliculus (SC; assessed using a fluorescent tracer) was no different than that of controls (D2-Gpnmb+ [D2-Gp], 10/10). The majority of untreated DBA/2J mice had severe reductions of labeling in the SC (13/20). The degree of optic nerve damage in corresponding eyes is indicated (E, NO = no damage, MOD = Moderate damage, SEV = Severe damage). (G) In contrast to untreated mice, 12-month-old Rad-D2 mice had normal PERG amplitudes. Untreated had reduced PERG amplitude by 9 months of age (n = 20 each group). Scale bars: 100 μm (B, top); 20 μm (B, bottom); 500 μm (E).