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Published on: March 23, 2016
Microglia Depletion leads to Increased Susceptibility to Ocular Hypertension-Dependent Glaucoma
Cory A Diemler1,2, Michael MacLean1, Sarah E Heuer1,3
1The Jackson Laboratory, Bar Harbor, ME.
Abstract:
In recent years, microglia have been highlighted for playing integral roles in neurodegenerative diseases, like glaucoma. To better understand the role of microglia during chronic ocular hypertension, we depleted microglia from aged (9-12 months old) DBA/2J (D2) mice, which exhibit age-related increases in intraocular pressure, using a dietary CSF1R antagonist, PLX5622. Retinal ganglion cell (RGC) somas were counted, and optic nerve cross-sections stained and assessed for glaucomatous damage. Sustained administration of dietary PLX5622 significantly reduced the numbers of retinal microglia. Dietary PLX5622 did not lead to changes in intraocular pressure in D2 or normotensive DBA/2J-Gpnmb+ (D2-Gpnmb+) control mice. While PLX5622-treated D2-Gpnmb+ did not develop optic nerve damage, PLX5622-treated D2 mice showed a significant increase in moderate-to-severe optic nerve damage compared to D2 mice fed a control diet. In conclusion, global reduction of microglia exacerbated glaucomatous neurodegeneration in D2 mice suggesting microglia play an overall beneficial role in protecting from ocular hypertension associated RGC loss.
Insights
Microglia depletion worsened glaucoma-related optic nerve damage in mice, suggesting these immune cells protect against retinal ganglion cell loss in ocular hypertension.
Area of Science:
- Neuroscience
- Immunology
- Ophthalmology
Background:
- Microglia, the resident immune cells of the central nervous system, are increasingly recognized for their complex roles in neurodegenerative diseases.
- Glaucoma, a leading cause of irreversible blindness, is characterized by progressive optic nerve damage and retinal ganglion cell (RGC) loss, often associated with elevated intraocular pressure (IOP).
Approach:
- This study investigated the role of microglia in experimental glaucoma using aged DBA/2J (D2) mice, a model exhibiting spontaneous ocular hypertension and glaucomatous damage.
- Microglia were depleted using a dietary CSF1R antagonist (PLX5622) to assess their impact on RGC survival and optic nerve integrity under chronic ocular hypertension.
- Intraocular pressure, RGC somas, and optic nerve damage were quantified in PLX5622-treated and control D2 mice, as well as in normotensive controls.
Key Points:
- Dietary PLX5622 effectively reduced retinal microglia numbers in D2 mice without altering intraocular pressure.
- Microglia depletion did not cause optic nerve damage in normotensive controls.
- In D2 mice, the reduction of microglia significantly exacerbated moderate-to-severe optic nerve damage compared to controls.
Conclusions:
- Global reduction of microglia exacerbates glaucomatous neurodegeneration in the DBA/2J mouse model.
- These findings suggest that microglia play a predominantly beneficial role in protecting against ocular hypertension-associated RGC loss and optic nerve damage.
- Targeting microglia may represent a potential therapeutic strategy for glaucoma, but their depletion could be detrimental.
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