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

Publication ,  Journal Article
Yu, C; Lad, EM; Mathew, R; Shiraki, N; Littleton, S; Chen, Y; Hou, J; Schlepckow, K; Degan, S; Chew, L; Amason, J; Kalnitsky, J; Proia, AD ...
Published in: J Exp Med
March 4, 2024

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.

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Published In

J Exp Med

DOI

EISSN

1540-9538

Publication Date

March 4, 2024

Volume

221

Issue

3

Location

United States

Related Subject Headings

  • Retinal Degeneration
  • Receptors, Immunologic
  • Microglia
  • Mice
  • Membrane Glycoproteins
  • Macrophages
  • Immunology
  • Humans
  • Galectin 3
  • Atrophy
 

Citation

APA
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Yu, C., Lad, E. M., Mathew, R., Shiraki, N., Littleton, S., Chen, Y., … Saban, D. R. (2024). Microglia at sites of atrophy restrict the progression of retinal degeneration via galectin-3 and Trem2. J Exp Med, 221(3). https://doi.org/10.1084/jem.20231011
Yu, Chen, Eleonora M. Lad, Rose Mathew, Nobuhiko Shiraki, Sejiro Littleton, Yun Chen, Jinchao Hou, et al. “Microglia at sites of atrophy restrict the progression of retinal degeneration via galectin-3 and Trem2.J Exp Med 221, no. 3 (March 4, 2024). https://doi.org/10.1084/jem.20231011.
Yu C, Lad EM, Mathew R, Shiraki N, Littleton S, Chen Y, et al. Microglia at sites of atrophy restrict the progression of retinal degeneration via galectin-3 and Trem2. J Exp Med. 2024 Mar 4;221(3).
Yu, Chen, et al. “Microglia at sites of atrophy restrict the progression of retinal degeneration via galectin-3 and Trem2.J Exp Med, vol. 221, no. 3, Mar. 2024. Pubmed, doi:10.1084/jem.20231011.
Yu C, Lad EM, Mathew R, Shiraki N, Littleton S, Chen Y, Hou J, Schlepckow K, Degan S, Chew L, Amason J, Kalnitsky J, Bowes Rickman C, Proia AD, Colonna M, Haass C, Saban DR. Microglia at sites of atrophy restrict the progression of retinal degeneration via galectin-3 and Trem2. J Exp Med. 2024 Mar 4;221(3).

Published In

J Exp Med

DOI

EISSN

1540-9538

Publication Date

March 4, 2024

Volume

221

Issue

3

Location

United States

Related Subject Headings

  • Retinal Degeneration
  • Receptors, Immunologic
  • Microglia
  • Mice
  • Membrane Glycoproteins
  • Macrophages
  • Immunology
  • Humans
  • Galectin 3
  • Atrophy