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Evidence supports the involvement of an important pathway in retinal ganglion cell dysfunction and death in traumatic optic neuropathy.
Reviewed by Wenbo Zhang, PhD
White blood cell recruitment seems to be the culprit in the inflammation following vision loss induced by trauma to the head. As in so many other serious disorders, limiting that inflammation might help prevent deterioration of the cellular function and loss of vision, said Wenbo Zhang, PhD.
“Traumatic head injury with concurrent damage to the optic nerve can cause traumatic optic neuropathy (TON) and resultant interruption of the transfer of information from the eyes to the brain,” said Dr. Zhang, associate professor, Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston. “This happens often in situations such as during war, an assault, the result of a motor vehicle accident, or any damage that causes tissue swelling and inflammation.”
These kinds of injuries not only can affect the optic nerve, but also can cause ganglion cell body loss.
With these types of injuries, the neurons are incapable of sending information and-depending on the degree of cellular loss-can result in complete irreversible blindness, according to Dr. Zhang.
The logical question that arises is: How can this situation be prevented or treated? he posed.
“Inflammation is the key player in retinal and neuronal damage,” Dr. Zhang said.
Inflammation is a two-edged sword in the body. On one hand, it is the body’s defense against injury and pathogens and can initiate wound healing.
However, sometimes there can be too much of a good thing if inflammation becomes out of control. In that situation, inflammation can be the body’s worst enemy by making the injury worse and causing apoptosis.
Mechanisms of inflammation
Mechanisms of inflammation
Dr. Zhang and colleagues wanted to investigate the mechanisms of inflammation in the death of retinal ganglion cells (RGCs). Leukocytes in the blood travel to the injury and help in repair the damaged tissue, he explained.
However, the very process that aids tissue repair is also “implicated in TON given that the levels of inflammatory molecules, including tumor necrosis factor-alpha and inducible nitric oxide synthase, are increased, inflammatory signaling pathways are activated, inflammatory cells (microglia/macrophages) are recruited to the site of axonal injury, and blocking tumor necrosis factor-alpha signaling substantially reduces RGC death in a mouse model of TON,” said the authors in their report (Ha et al. Am J Pathol. 2017;187:352-365).
The details of leukocyte recruitment in the retina and its contribution to RGC damage are unknown, however.
Investigators used a mouse model of TON in which they induced a crush injury in the optic nerve in the right eyes of the animals and observed what happened afterward at various time points.
In this model, Dr. Zhang reported an interesting phenomenon in that at 9 hours following the injury, imaging showed a “dramatic increase in leukocyte rolling and adhesion in the veins near the optic nerve. We found evidence that vascular inflammation is a component in optic nerve injury.”
Interestingly, 24 hours after the injury was induced, there was no significant loss of the RGC bodies, but the infiltration by the leukocytes was massive.
However, by 7 days later, investigators found significant RCG loss. This prompted them to examine several chemokines-proteins that are secreted by injured tissue during infection or inflammation-that might be instrumental in the late-stage effects of inflammation by recruiting leukocytes to the injured area.
Specifically, the chemokine, CXCL10, was found to recruit the leukocytes after binding to it receptor C-X-C chemokine receptor (CXCR) 3. The levels of the chemokine and the receptor were found to be markedly elevated in TON, he explained.
“This pathway is critical to the inflammation in many diseases, such as arthritis, stroke, and diabetic retinopathy, and we believe that it may be related to RGC injury following tissue damage,” Dr. Zhang said.
When investigators manipulated the murine model by deleting CXCR3 in the leukocytes and effectively disrupting the pathway, they observed there were significantly fewer leukocytes present at the injury site and RGC death was prevented 7 days after the tissue was damaged, he noted.
A further step in this research was blockade of CXCR3 by using AMG 487, which is a CXCR3 antagonist. They found this treatment route was neuroprotective after TON occurred and was not toxic.
“AMG 487 treatment partially prevented RGC loss at 7 days after development of TON. These data suggest that pharmacological blockade of CXCR3 is a promising approach for neuroprotection after TON,” the investigators reported.
“This treatment is a potential new way to treat TON,” Dr. Zhang added.
Given that certain diseases that are characterized by inflammation might benefit from disruption of the pathway leading to RGC dysfunction and death, Dr. Zhang and team are theorizing that patients with optic neuritis, such as multiple sclerosis, might benefit down the line.
“We believe that the CXCL10/CXCR3 pathway is involved in this disease but we need additional support to forward our research,” Dr. Zhang said.
Wenbo Zhang, PhD
Dr. Zhang has no financial interest in any aspect of this report.