Abstract
Purpose:
A self-perpetuating process of neuronal degeneration takes place in the retina following mechanical or biochemical insults to the eye or optic nerve. Monocyte-derived macrophages have been identified as important players in arresting this process. Since the eye is an immune-privileged site, endowed with specialized barriers to preserve its integrity, we hypothesized that the entry route of immune cells to the eye dictates their fate. Specifically, we envisioned that “healing” monocyte-derived macrophages enter the eye through the retinal pigment epithelium (RPE).
Methods:
C57BL/6J mice were subjected to either acute biochemical or mechanical injury (retinal glutamate intoxication or optic nerve crush, respectively). Monocyte augmentation was accomplished by either intravenous or intravitreal adoptive transfer, or by CNS-based neuroprotective vaccination. The RPE response to injury and the interaction of monocytes with the RPE and retina were monitored by immunohistochemistry, quantitative Real Time PCR, flow cytometry and live imaging.
Results:
Monocytes, injected either intravenously or intravitreally following glutamate intoxication to the retina, conferred retinal ganglion cell protection. The injected monocytes localized to the site of damage, as well as to the subretinal space, adjacent to the RPE. Mechanical injury in the form of optic nerve crush resulted in immune cell infiltration into the retina, which was further augmented under experimental manipulations that lead to better neuronal survival. The RPE responded to injury with the elevated expression of adhesion and trafficking molecules. Live imaging showed the sequential accumulation of monocytes in the RPE and retina after ONC.
Conclusions:
Our results emphasize the relationship between the activation of the RPE for leukocyte trafficking and the recruitment of monocyte-derived macrophages, which display a beneficial effect within the retina following injury. They further highlight the possibility that the RPE serves as a selective and educative gateway for “healing” immune cell recruitment to the retina, similar to the role displayed by the brain’s choroid plexus in the context of CNS injury.