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 their viability.
Highlights
Protein synthesis can outpace protein folding in rapidly dividing cells, leading to accumulation of unfolded proteins in the endoplasmic reticulum (ER) [1, 2]
This programmed cell removal (PrCR) is associated with expression of chemotactic and inflammatory cytokines linked to migration of myeloid cells into the outer nuclear layer (ONL) of photoreceptors and to the danger-associated molecular pattern (DAMP), CALR, which acts as a myeloid recognition signal on the rod cell surface
We provide evidence that PrCR of live rods contributes to loss of the photoreceptors in pig retinitis pigmentosa (RP)
Summary
Sang Joon Lee1,2,‡, Wei Wang1,‡, Lei Jin, Xiaoqin Lu1,4, Lei Gao, Yao Chen, Tingting Liu, Douglas Emery, Eric Vukmanic, Yongqing Liu, Henry J. Dean1,4,* From the 1Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, Kentucky, USA; 2Department of Ophthalmology, Kosin University College of Medicine, Seo-gu, Busan, Korea; 3Department of Ophthalmology, The Third People’s Hospital of Dalian, Dalian Medical University, Dalian, China; 4Department of Medicine, University of Louisville Health Sciences Center, Louisville, Kentucky, USA; 5Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing, China; and 6Department of Ophthalmology, Xiangya Hospital, Central South University, Changsha, China
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