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

James R. Tribble,J. Harder,Pete A. Williams,S. John

Published 2019 in bioRxiv

ABSTRACT

Background 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. Methods 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-). Transcriptomic profiles were compared to other published optic nerve head datasets to assess the contribution of microglia to the signatures discovered in these published data. Furthermore, RNA-sequencing was performed on optic nerve head microglia from mice treated with radiation therapy, a potent therapy preventing neuroinflammatory insults. Results Transcriptomic profiling of optic nerve head microglia mRNA identifies early metabolic priming with marked changes to mitochondria-derived RNA expression, and changes to phagocytosis, inflammatory, and sensome pathways. 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, radiation therapy of DBA/2J mice potently abolishes these microglia metabolic transcriptomic changes at the same time points. Conclusions Microglia become metabolically primed early in glaucoma pathogenesis with suppression of homeostatic regulation including phagocytosis, inflammatory, and sensome pathways. These changes are largely prevented by radiation therapy. Neuroinflammatory signatures in DBA/2J glaucoma likely arise from infiltrating monocytes and not from activated or proliferative microglia at this early time point. In addition, our data provide a unique resource for the community to help drive further hypothesis generation and testing.

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