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

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

doi:10.1172/JCI61135

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

Journal article

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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, Ileana Soto, Xianjun Zhu, Margaret Ryan, Danilo G Macalinao, Gregory L Sousa, Lura B Caddle, Katharine H MacNicoll, Jessica M Barbay, Vittorio Porciatti, …

The Journal of clinical investigation, Vol.122(4), pp.1246-1261

04/02/2012

DOI: 10.1172/JCI61135

PMCID: PMC3314470

PMID: 22426214

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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.

Details

Title: Subtitle: Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma
Creators: Gareth R Howell - Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine, USA
Ileana Soto - Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine, USA
Xianjun Zhu - Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine, USA
Margaret Ryan - Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine, USA
Danilo G Macalinao - Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine, USA
Gregory L Sousa - Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine, USA
Lura B Caddle - Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine, USA
Katharine H MacNicoll - Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine, USA
Jessica M Barbay - Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine, USA
Vittorio Porciatti - Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine, USA
Michael G Anderson - Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine, USA
Richard S Smith - Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine, USA
Abbot F Clark - Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine, USA
Richard T Libby - Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine, USA
Simon W.M John - Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine, USA
Resource Type: Journal article
Publication Details: The Journal of clinical investigation, Vol.122(4), pp.1246-1261
DOI: 10.1172/JCI61135
PMID: 22426214
PMCID: PMC3314470
NLM abbreviation: J Clin Invest
ISSN: 0021-9738
eISSN: 1558-8238
Publisher: American Society for Clinical Investigation
Language: English
Date published: 04/02/2012
Academic Unit: Molecular Physiology and Biophysics; Ophthalmology and Visual Sciences
Record Identifier: 9984025405402771

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