Microglia implicated in inherited retinitis pigmentosa

Retinal microglia contribute to rod demise in retinitis pigmentosa-a blinding hereditary retinal disease for which there is currently no approved treatment, according to a recent study.

Typically, rod photoreceptors in retinitis pigmentosa degenerate as a result of genetic mutations. Unfortunately, more than 100 possible diverse genes have been implicated, which means that gene therapy-while promising-remains a distant and impractical dream in many cases.

Results of this new study-published in EMBO Molecular Medicine-raise the prospect of retinal microglia providing a future target for novel therapeutic approaches that will defer photoreceptor loss and associated loss of vision.

Microglia-glial cells that function as macrophages in the central nervous system-represent the endogenous brain defence and immune system. Microglial migration is essential for immune defence and wound healing, and microglial phagocytosis plays a key role in removing apoptotic cells.

In response to a neurological lesion, microglia accumulate at the damaged site and remove cellular debris and even parts of damaged cells. Further, it has recently been discovered that microglial phagoptosis (phagocytosis of a living cell) is also a primary cause of neuronal cell death.

Researchers led by Wai T. Wong, MD, PhD-chief, neuron-glial interactions in retinal diseases, National Eye Institute, National Institutes of Health, Bethesda, MD-examined interactions between retinal microglia and photoreceptors throughout the course of retinal degeneration to uncover the underlying cellular mechanisms involved.

They primarily studied mice with a mutation in the rod photoreceptor gene Pde6b that is known to also cause retinitis pigmentosa in humans.

Results

In retinitis pigmentosa, the mutations induce cellular stress in non-apoptotic rod photoreceptors and cause the production of phatidylserine, which is known as the ‘eat-me’ signal. This marks the rod as a target for phagocytosis by the microglia, even though the cell-if left alone-would continue to be viable.

Next: What the researched noticed early on

The researchers noticed that early in the clinical course of retinitis pigmentosa, microglia infiltrated the outer nuclear layer (ONL) of the retina-from which they are usually excluded-and became activated to destroy non-apoptotic, living, rod photoreceptors. This destruction occurred by a process of dynamic physical contact and engulfment, which was captured on video.

The live time-lapse imaging revealed a fascinating process whereby the microglia approached selected cells then dynamically probed, partially enveloped, released and retreated from them over a period of about 10 to 15 minutes before engulfing them and internalising them completely in the form of a phagosome.

The absorption occurred in different ways: in some cases, the microglia formed a ‘cup’ structure that probed then surrounded the photoreceptor somata, while other photoreceptors were engulfed by lamellipodial microglial processes without the involvement of a defined phagocytic cup.

Even the minority of cone photoreceptors that expressed phatidylserine (‘eat-me’) were mainly ignored by the microglia, which matches the known disease course.

Microglia were genetically depleted from the retina in an experiment to confirm their involvement in retinal degeneration. The microglia-depleted mice showed significantly less ONL degeneration than controls, with correspondingly better visual function. Similarly, when microglial phagocytosis was chemically inhibited in one eye, the ONL was preserved compared with the other (control) eye and electroretinography responses were also better.

As well as consuming stressed but living rods, activated microglia upregulate production of IL-1b. The pro-inflammatory mechanisms so induced potentiate rod stress and apoptosis, which creates a positive feedback loop and further accelerates retinal degeneration.

Similar results were obtained using other mouse models and human laboratory specimens, confirming the involvement of microglia in retinitis pigmentosa that has arisen as a result of different genetic mutations.

Next: What this means

This suggests that therapies targeting retinal microglia should have broad potential to defer the irreversible vision loss experienced by patients with retinitis pigmentosa.