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Mapping the origin and fate of myeloid cells in distinct compartments of the eye by single-cell profiling

ABSTRACT: Similar to the brain, the eye is considered an immune-privileged organ where tissue-resident macrophages provide the major immune cell constituents. However, little is known about spatially restricted macrophage subsets within different eye compartments with regard to their origin, function and fate during health and disease. Here, we combined single-cell analysis, fate mapping, parabiosis and computational modelling to comprehensively examine myeloid subsets in distinct parts of the eye during homeostasis. This approach allowed us to identify myeloid subsets displaying diverse transcriptional states. During choroidal neovascularization, a typical hallmark of neovascular age-related macular degeneration (AMD), we recognized disease-specific macrophage subpopulations with distinct molecular signatures. Our results highlight the heterogeneity of myeloid subsets and their dynamics in the eye. This provides new insights into the innate immune system in this organ and may offer new therapeutic targets for ophthalmological diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE160797 | GEO | 2021/01/19

REPOSITORIES: GEO

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Project description:AbstractBlindness or vision loss due to neuroretinal and photoreceptor degeneration affects millions of individuals worldwide. In numerous neurodegenerative diseases, including age related macular degeneration, dysregulated immune response mediated retinal degeneration have been found to play a critical role in the disease pathogenesis. To better understand the pathogenic mechanisms underlying the retinal degeneration, we used a mouse model of systemic immune activation where we infected mice with lymphocytic choriomeningitis virus (LCMV) clone 13. Here we evaluated the effects of LCMV infection and present a comprehensive discovery-based proteomic investigation using tandem mass tag (TMT) labelling and high-resolution liquid chromatography - tandem mass spectrometry (LC-MS/MS). Changes in protein regulation in the posterior part of the eye, neuroretina and RPE/choroid, were compared to spleen as a secondary lymphoid organ and to the kidney as a non-lymphoid but encapsulated organ at 1, 8 and 28 weeks of infection. Using bioinformatic tools, we found several proteins responsible for maintaining normal tissue homeostasis to be differentially regulated in the neuroretina and the RPE/choroid during the degenerative process. Additionally, in the organs we observed several important protein pathways contributing to cellular homeostasis and tissue development to be perturbed and associated with LCMV mediated inflammation promoting disease progression. Our findings suggest that the response to a systemic chronic infection differs between neuroretina, and the RPE/choroid and the processes induced by chronic systemic infection in RPE/choroid are not unlike those induced in non-immune privileged organs such as the kidney and spleen. Overall, our data provides detailed insight into several molecular mechanisms of retinal degeneration and highlights various novel proteins pathways which further suggest that the posterior part of the eye is not an isolated immunological entity despite of the existence of neuroretinal immune privilege.

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Mapping the origin and fate of myeloid cells in distinct compartments of the eye by single-cell profiling

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