Glaucoma is the leading cause of irreversible blindness affecting almost 80 million patients worldwide. Recent work has demonstrated critical early neuroinflammatory insults occur in the optic nerve head (where retinal ganglion cells that make up the optic nerve exit the eye) following ocular hypertension, a major risk factor.
Microglia and infiltrating monocytes are likely candidates to drive these neuroinflammatory insults. However, the exact molecular identity of microglia following ocular hypertensive insults is unknown.
Site for early glaucoma damage
Since the optic nerve head has been identified as a critical site for early glaucoma damage, the collaborating research teams sought to identify the earliest changes to microglia residing there.
Using RNA sequencing of microglia, a powerful technology that detects the level at which genes are expressed, glaucomatous and control mice were compared. The result was then compared to existing data previously generated on monocytes.
Additional experiments on radiation treatment
Additional experiments were conducted to compare mice that received radiation treatment before developing glaucoma. Radiation, targeted at the eye, has been shown in animal models to prevent early inflammatory processes and prevent the entry of monocytes into the retina.
Photo: Stefan Zimmerman
"We found that contrary to our expectations, microglia in early glaucomatous optic nerve heads were not pro-inflammatory, but instead had lower expression of genes associated with initiating inflammatory responses. Importantly, the microglia also showed changes to expression of genes involved in cell metabolism," says James Tribble, postdoctoral researcher at St. Erik Eye Hospital and Karolinska Institutet, who led the study carried out in collaboration with Howard Hughes Medical Institute, Columbia University Medical Center, and the Jackson Laboratory.
Dysregulated metabolism in retinal ganglion cells
Previously, the researchers discovered dysregulated metabolism in retinal ganglion cells, the axons of which make up the optic nerve.
"Our findings suggest that rather than becoming activated and damaging very early in glaucoma, microglia in the optic nerve head instead experience dysregulation of a number of their important functions. Radiation treatment prevented these changes from occurring. Comparing with monocytes showed that this early inflammation is likely initially derived from monocytes, and not microglia," says Assistant Professor Pete Williams at Karolinska Institutet and St. Erik Eye Hospital, one of the corresponding authors.
Novel understanding of early glaucomatous damage
The study shows that timing is everything as very early on in disease, different cell types are experiencing different changes and react in different and maybe opposing ways.
"For existing patients, these findings will not translate in to any immediate benefits, but they do help us better understand the very earliest processes that could be targeted to delay or prevent glaucomatous damage," says James Tribble.
Further on, researchers will continue to look at how and where the earliest gene changes occur in the different cell types of the retina that interact with retinal ganglion cells. This will help to identify therapies that have common targets across multiple cell types involved in glaucoma.
The study was financed by the Barbra and Joseph Cohen Foundation, Columbia University, the Swedish Research Council, the Howard Hughes Medical Institute, Karolinska Institutet and St. Erik Eye Hospital philanthropic donations.
"Ocular hypertension suppresses homeostatic gene expression in optic nerve head microglia of DBA/2J mice", James R Tribble, Jeffrey M Harder, Pete A Williams, Simon W M John, Molecular Brain, online 26 May, 2020, doi: 10.1186/s13041-020-00603-7