Microglia at sites of atrophy restrict the progression of retinal degeneration via galectin-3 and Trem2

• DOI: 10.1084/jem.20231011
• Publication Date: 2024-01-30T14:50:52Z
• Authors: Chen Yu; Eleonora M. Lad; Rose Mathew; Nobuhiko Shiraki; Sejiro Littleton; Yun Chen; Jinchao Hou; Kai Schlepckow; Simone Degan; Lindsey Chew; Joshua Amason; Joan Kalnitsky; Catherine Bowes R...; Alan D. Proia; Marco Colonna; Christian Haass; Daniel R. Saban
• Keywords: Membrane Glycoproteins; Galectin 3; Macrophages; Retinal Degeneration; ICTS (Institute of Clinical and Translational Sciences); genetics [Galectin 3]; Article; Mice; Trem2 protein, mouse; genetics [Membrane Glycoproteins]; Immunologic; Receptors; Medicine and Health Sciences; Lgals3 protein, mouse; genetics [Receptors, Immunologic]; Animals; Humans; ddc:610; Microglia; Atrophy; Receptors, Immunologic; Aged

Outer retinal degenerations, including age-related macular degeneration (AMD), are characterized by photoreceptor and retinal pigment epithelium (RPE) atrophy. In these blinding diseases, macrophages accumulate at atrophic sites, but their ontogeny and niche specialization remain poorly understood, especially in humans. We uncovered a unique profile of microglia, marked by galectin-3 upregulation, at atrophic sites in mouse models of retinal degeneration and human AMD. In disease models, conditional deletion of galectin-3 in microglia led to phagocytosis defects and consequent augmented photoreceptor death, RPE damage, and vision loss, indicating protective roles. Mechanistically, Trem2 signaling orchestrated microglial migration to atrophic sites and induced galectin-3 expression. Moreover, pharmacologic Trem2 agonization led to heightened protection but in a galectin-3–dependent manner. In elderly human subjects, we identified this highly conserved microglial population that expressed galectin-3 and Trem2. This population was significantly enriched in the macular RPE-choroid of AMD subjects. Collectively, our findings reveal a neuroprotective population of microglia and a potential therapeutic target for mitigating retinal degeneration.