title: 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.affiliation: Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine 04609, USA.
authors.forename: Gareth R
authors.initials: GR
authors.lastname: Howell
authors.forename: Ileana
authors.initials: I
authors.lastname: Soto
authors.forename: Xianjun
authors.initials: X
authors.lastname: Zhu
authors.forename: Margaret
authors.initials: M
authors.lastname: Ryan
authors.forename: Danilo G
authors.initials: DG
authors.lastname: Macalinao
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Sousa
authors.forename: Lura B
authors.initials: LB
authors.lastname: Caddle
authors.forename: Katharine H
authors.initials: KH
authors.lastname: MacNicoll
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Barbay
authors.forename: Vittorio
authors.initials: V
authors.lastname: Porciatti
authors.forename: Michael G
authors.initials: MG
authors.lastname: Anderson
authors.forename: Richard S
authors.initials: RS
authors.lastname: Smith
authors.forename: Abbot F
authors.initials: AF
authors.lastname: Clark
authors.forename: Richard T
authors.initials: RT
authors.lastname: Libby
authors.forename: Simon W M
authors.initials: SW
authors.lastname: John
mesh_terms: D000818:Animals; D001369:Axons / Q000648:ultrastructure; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology; D016371:Cranial Irradiation; D004195:Disease Models, Animal; D019333:Endothelin-2 / Q000494:pharmacology / Q000502:physiology / Q000633:toxicity; D005720:Gamma Rays; D005786:Gene Expression Regulation; D005901:Glaucoma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D007429:Intraocular Pressure / Q000528:radiation effects; D019041:L-Selectin / Q000502:physiology; D051379:Mice; D008811:Mice, Inbred DBA; D009000:Monocytes / Q000502:physiology*; D016501:Neurites / Q000648:ultrastructure; D009898:Optic Disk / Q000473:pathology* / Q000528:radiation effects; D011828:Radiation Chimera; D011879:Radiotherapy Dosage; D012165:Retinal Ganglion Cells / Q000473:pathology / Q000528:radiation effects*; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects*; D015854:Up-Regulation / Q000528:radiation effects; D014916:Whole-Body Irradiation; D014965:X-Rays
chemical_list: D015815:Cell Adhesion Molecules; D019333:Endothelin-2; D019041:L-Selectin