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bioRxiv · 10.1101/856427

Suppression of homeostatic gene expression and increased expression of metabolism-related genes are early features of glaucoma in optic nerve head microglia

Tribble, J. R.·Harder, J. M.·Williams, P. A.·John, S. W.
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Abstract

Glaucoma is the leading cause of irreversible vision loss. Ocular hypertension is a major risk factor for glaucoma and recent work has demonstrated critical early neuroinflammatory insults occur in the optic nerve head following ocular hypertension. Microglia and infiltrating monocytes are likely candidates to drive these neuroinflammatory insults. However, the exact molecular identity / transcriptomic profile of microglia early following ocular hypertensive insults is unknown. To elucidate the molecular identity of microglia during early glaucoma pathogenesis, we performed RNA-sequencing of microglia mRNA from the optic nerve head of a genetic mouse model of glaucoma (DBA/2J) at a time point following ocular hypertensive insults, but preceding detectable neurodegeneration (with microglia identified as being CD45lo/CD11b+/CD11c-). Furthermore, RNA-sequencing was performed on optic nerve head microglia from mice treated with radiation therapy, a potent therapy preventing neuroinflammatory insults. Transcriptomic profiling of optic nerve head microglia mRNA identifies early metabolic priming with marked changes in mitochondrial gene expression, and changes to phagocytosis, inflammatory, and sensome pathways. The data predict that many functions of microglia that help maintain tissue homeostasis are affected. Comparative analysis of these data with data from previously published whole optic nerve head tissue or monocyte-only samples from DBA/2J mice demonstrate that many of the neuroinflammatory signatures in these data sets arise from infiltrating monocytes and not reactive microglia. Finally, our data demonstrate that radiation therapy of DBA/2J mice potently abolishes these microglia metabolic transcriptomic changes at the same time points. Together, our data provide a unique resource for the community to help drive further hypothesis generation and testing in glaucoma.

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Tribble, J. R., Harder, J. M., Williams, P. A., John, S. W.. 2019-11-26. Suppression of homeostatic gene expression and increased expression of metabolism-related genes are early features of glaucoma in optic nerve head microglia. https://doi.org/10.1101/856427

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