Abstract
BackgroundGlaucoma is one of the leading causes of irreversible blindness in the world. The major risk factor is elevated intraocular pressure (IOP) leading to progressive retinal ganglion cell (RGC) death from the optic nerve (ON) to visual pathways in the brain. Glaucoma has been reported to share mechanisms with neurodegenerative disorders. We therefore hypothesize that neuroinflammatory mechanisms in central visual pathways may contribute to the spread of glaucoma disease. The aim of the present study was to analyze the neuroinflammation processes that occur from the pathological retina to the superior colliculi (SCs) in a rat model of unilateral ocular hypertension induced by episcleral vein cauterization (EVC).ResultsSix weeks after unilateral (right eye) EVC in male Long-Evans rats, we evaluated both the neurodegenerative process and the neuroinflammatory state in visual pathway tissues. RGCs immunolabeled (Brn3a+) in ipsilateral whole flat-mounted retina demonstrated peripheral RGC loss associated with tissue macrophage/microglia activation (CD68+). Gene expression analysis of hypertensive and normotensive retinas revealed a significant increase of pro-inflammatory genes such as CCL2, IL-1β, and Nox2 mRNA expression compared to naïve eyes. Importantly, we found an upregulation of pro-inflammatory markers such as IL-1β and TNFα and astrocyte and tissue macrophage/microglia activation in hypertensive and normotensive RGC projection sites in the SCs compared to a naïve SC. To understand how neuroinflammation in the hypertensive retina is sufficient to damage both right and left SCs and the normotensive retina, we used an inflammatory model consisting in an unilateral stereotaxic injection of TNFα (25 ng/μl) in the right SC of naïve rats. Two weeks after TNFα injection, using an optomotor test, we observed that rats had visual deficiency in both eyes. Furthermore, both SCs showed an upregulation of genes and proteins for astrocytes, microglia, and pro-inflammatory cytokines, notably IL-1β. In addition, both retinas exhibited a significant increase of inflammatory markers compared to a naïve retina.ConclusionsAll these data evidence the complex role played by the SCs in the propagation of neuroinflammatory events induced by unilateral ocular hypertension and provide a new insight into the spread of neurodegenerative diseases such as glaucoma.
Highlights
Glaucoma is one of the leading causes of irreversible blindness in the world
Ocular hypertension leads to retinal ganglion cell (RGC) death in the cauterized eye and affects the contralateral eye intraocular pressure (IOP) was measured with a tonometer and followed once a week for 40 days
We did not observe any loss of RGC in the middle and central retina in HT eyes compared with naïve eyes
Summary
The major risk factor is elevated intraocular pressure (IOP) leading to progressive retinal ganglion cell (RGC) death from the optic nerve (ON) to visual pathways in the brain. Glaucoma is a chronic degenerative optic neuropathy in which intraocular pressure (IOP) is abnormally elevated, leading to the progressive loss of retinal ganglion cells (RGCs) and an alteration of their axons. Abnormal activation of autoimmunity has been observed, which could induce the loss of RGCs in glaucoma patients without elevated IOP [5]. This disease may progress through an IOP-independent mechanism and may involve other factors. It has been recently demonstrated that a deregulation of cytokine signaling in the SC can appear before the IOP or axonal degeneration in the DBA/2J mouse glaucoma model [18]
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