Rod photoreceptor clearance due to misfolded rhodopsin is linked to a DAMP-immune checkpoint switch.

The Journal of Biological Chemistry
Sang Joon LeeDouglas C Dean

Abstract

Chronic endoplasmic reticulum stress resulting from misfolding of the visual pigment rhodopsin (RHO) can lead to loss of rod photoreceptors, which initiates retinitis pigmentosa, characterized initially by diminished nighttime and peripheral vision. Cone photoreceptors depend on rods for glucose transport, which the neurons use for assembly of visual pigment-rich structures; as such, loss of rods also leads to a secondary loss of cone function, diminishing high-resolution color vision utilized for tasks including reading, driving, and facial recognition. If dysfunctional rods could be maintained to continue to serve this secondary cone preservation function, it might benefit patients with retinitis pigmentosa, but the mechanisms by which rods are removed are not fully established. Using pigs expressing mutant RHO, we find that induction of a danger-associated molecular pattern (DAMP) "eat me" signal on the surface of mutant rods is correlated with targeting the live cells for (PrCR) by retinal myeloid cells. Glucocorticoid therapy leads to replacement of this DAMP with a "don't eat me" immune checkpoint on the rod surface and inhibition of PrCR. Surviving rods then continue to promote glucose transport to cones, maintaining the...Continue Reading

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