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

• Published in: The Journal of experimental medicine Vol. 221; no. 3
• Main Authors: Yu, Chen, Lad, Eleonora M., Mathew, Rose, Shiraki, Nobuhiko, Littleton, Sejiro, Chen, Yun, Hou, Jinchao, Schlepckow, Kai, Degan, Simone, Chew, Lindsey, Amason, Joshua, Kalnitsky, Joan, Bowes Rickman, Catherine, Proia, Alan D., Colonna, Marco, Haass, Christian, Saban, Daniel R.
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 04.03.2024
• Subjects: Innate Immunity and Inflammation; Neuroinflammation; Neuroscience
• ISSN: 0022-1007; 1540-9538; 1540-9538
• DOI: 10.1084/jem.20231011

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.