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Journal article
Phagocytosis in the retina promotes local insulin production in the eye
NATURE METABOLISM, v 5(2), p207
Feb 2023
PMID: 36732622
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Retinal pigment epithelial cells are identified as a local source of insulin in the retina, which is stimulated by phagocytosis of photoreceptor outer segments and starvation and has the potential to influence retinal physiology and disease. The retina is highly metabolically active, relying on glucose uptake and aerobic glycolysis. Situated in close contact to photoreceptors, a key function of cells in the retinal pigment epithelium (RPE) is phagocytosis of damaged photoreceptor outer segments (POS). Here we identify RPE as a local source of insulin in the eye that is stimulated by POS phagocytosis. We show that Ins2 messenger RNA and insulin protein are produced by RPE cells and that this production correlates with RPE phagocytosis of POS. Genetic deletion of phagocytic receptors ('loss of function') reduces Ins2, whereas increasing the levels of the phagocytic receptor MerTK ('gain of function') increases Ins2 production in male mice. Contrary to pancreas-derived systemic insulin, RPE-derived local insulin is stimulated during starvation, which also increases RPE phagocytosis. Global or RPE-specific Ins2 gene deletion decreases retinal glucose uptake in starved male mice, dysregulates retinal physiology, causes defects in phototransduction and exacerbates photoreceptor loss in a mouse model of retinitis pigmentosa. Collectively, these data identify RPE cells as a phagocytosis-induced local source of insulin in the retina, with the potential to influence retinal physiology and disease.
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Details
- Title
- Phagocytosis in the retina promotes local insulin production in the eye
- Publication Details
- NATURE METABOLISM, v 5(2), p207
- Publisher
- NATURE PORTFOLIO; BERLIN
- Grant note
- We thank members of the Ravichandran laboratory as well as B. Gelfand and R. Lindsay for input and critical reading of the manuscript. We thank E. Thorpe and I. Tabas for the MerTKCR mice, J. Mandell for human retinal samples and E. Nandrot and R. Rajala for advice on specific protocols. Figure schematics were created using BioRender images as templates. This work was supported by grants to K.S.R. from the National Institute of General Medical Sciences (R35GM122542), National Institute of Allergy and Infectious Diseases (R01AI159551), the National Heart, Lung and Blood Institute (P01HL120840), the Center for Cell Clearance/University of Virginia and Bone and Joint Canada Investigator funds from the Washington University School of Medicine to J.I.E. via NEI F32 (EY031211) and T32AI7496-23. J.A. is a cofounder of DiceRx, iVeena Holdings, iVeena Delivery Systems, and Inflammasome Therapeutics; has been a consultant for Abbvie, Boehringer-Ingelheim, Olix Pharmaceuticals, Retinal Solutions, and Saksin LifeSciences; and is named as an inventors on patent applications filed by his university, all unrelated to this work. J.A. has received support from the UVA Strategic Investment Fund, National Institutes of Health (NIH) grants (R01EY028027, R01EY029799, R01EY031039, R01AG082108), DuPont Guerry, III, Professorship, and a gift from Mr. and Mrs. Eli W. Tullis.
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Drexel University
- Web of Science ID
- WOS:000924683100001
- Scopus ID
- 2-s2.0-85147294422
- Other Identifier
- 991021861187104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Endocrinology & Metabolism