Dendritic cells migrate to regions of retinal stress to mediate neurodegeneration

June 28, 2018

Editor’s Note: Ophthalmology Times is pleased to announce

Editor’s Note: Ophthalmology Times is pleased to announce Peter H. Tang, MD, PhD, vitreoretinal surgery fellow, Stanford University Byers Eye Institute, Palo Alto, CA, as the second-place honoree of the inaugural Ophthalmology Times Research Scholar Honoree Program. Dr. Tang’s abstract is featured here.

The Ophthalmology Times Research Scholar Honoree Program is dedicated to the education of retina fellows and residents by providing a unique opportunity for fellows/residents to share notable research and challenging cases with their peers and mentors. The program is supported by unrestricted grants from Regeneron Pharmaceuticals and Carl Zeiss Meditec Inc.

Elizabeth Atchison, MD, senior fellow, Rush University and Illinois Retina Associates Chicago, is the first-place honoree of the Ophthalmology Times Research Scholar Honoree Program. Her abstract is featured at ModernRetina.com/Atchison. Look for more case study honorees in future issues.

 

Background

RPE65 protein dysfunction disrupts retinal metabolism of vitamin A leading to Leber congenital amaurosis (LCA), a congenital retinal dystrophy characterized by early-onset cone death and progressive vision loss. Human LCA is recapitulated in the RPE65 gene knockout (RPE65-/-) mice.

Previous studies of mice with genetically engineered dendritic cells (DCs) expressing green fluorescent protein (GFP) show that these cells were attracted to retinal injury. In our study, we asked if apoptotic photoreceptor cell death in RPE65-/- mice induced a retinal response that involved these DCs.

Methods

RPE65-/- mice with DC expressing GFP were generated through cross-breeding and analyzed by immunohistochemistry, confocal microscopy, fluorescence funduscopy, and flow cytometry. Tamoxifen was used to deplete DC in separate sensitive RPE65-/- mice to investigate the potential role of DC in LCA.

Results

DCs were found to concentrate in the photoreceptor cell layers coinciding with the peak of cone death at 2 to 3 weeks of age. Elevated numbers of DC remained in RPE65-/- retinas after the first month of age, suggesting that other factors, possibly rod degeneration, may play roles in recruiting and retaining DC cells in the outer retina. Sustained tamoxifen-mediated depletion of DC in the RPE65-/- mice from day 7 to 41 of age accelerated cone death.

Conclusion

Our results show that DCs are recruited to the sites of retinal injury and stress. DC in an animal model of LCA show migration to the outer retina by cone death due to disruption of intrinsic retinoid metabolism. The presence and activity of these cells may have implications for novel therapeutics involving immune cells in the treatment for congenital retinal dystrophies.