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    Microglia implicated in inherited retinitis pigmentosa


    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

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