Melanophages give rise to hyperreflective foci in AMD, a disease-progression marker

• Published in: Journal of neuroinflammation Vol. 20; no. 1; p. 28
• Main Authors: Augustin, Sebastien, Lam, Marion, Lavalette, Sophie, Verschueren, Anna, Blond, Frédéric, Forster, Valérie, Przegralek, Lauriane, He, Zhiguo, Lewandowski, Daniel, Bemelmans, Alexis-Pierre, Picaud, Serge, Sahel, José-Alain, Mathis, Thibaud, Paques, Michel, Thuret, Gilles, Guillonneau, Xavier, Delarasse, Cécile, Sennlaub, Florian
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 08-02-2023; BioMed Central; BMC
• Subjects: Age; Age-related macular degeneration; Analysis; Animals; Antibodies; Biological markers; Biomarkers; Bone marrow; Bone marrow transplantation; Care and treatment; CD47; CD47 Antigen - metabolism; Development and progression; Haplotypes; Humans; Leukocytes (mononuclear); Life Sciences; Macrophage; Macrophages; Macular degeneration; Macular Degeneration - metabolism; Melanosomes; Mice; Mutation; Neuroinflammation; Phagocytes; Photoreceptors; Retina; Retina - metabolism; Retinal Pigment Epithelium - metabolism; Risk factors; Scanning electron microscopy; Tomography; Tomography, Optical Coherence - methods; Transplantation; France; Fiji; Neuroinflammation; CD47; Age-related macular degeneration; Macrophage
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-023-02699-9

Retinal melanosome/melanolipofuscin-containing cells (MCCs), clinically visible as hyperreflective foci (HRF) and a highly predictive imaging biomarker for the progression of age-related macular degeneration (AMD), are widely believed to be migrating retinal pigment epithelial (RPE) cells. Using human donor tissue, we identify the vast majority of MCCs as melanophages, melanosome/melanolipofuscin-laden mononuclear phagocytes (MPs). Using serial block-face scanning electron microscopy, RPE flatmounts, bone marrow transplantation and in vitro experiments, we show how retinal melanophages form by the transfer of melanosomes from the RPE to subretinal MPs when the "don't eat me" signal CD47 is blocked. These melanophages give rise to hyperreflective foci in Cd47
-mice in vivo, and are associated with RPE dysmorphia similar to intermediate AMD. Finally, we show that Cd47 expression in human RPE declines with age and in AMD, which likely participates in melanophage formation and RPE decline. Boosting CD47 expression in AMD might protect RPE cells and delay AMD progression.