Journal Article

DZNE-2024-00115

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Microglia at sites of atrophy restrict the progression of retinal degeneration via galectin-3 and Trem2.

Yu, C. ; Lad, E. M. ; Mathew, R. ; Shiraki, N. ; Littleton, S. ; Chen, Y. ; Hou, J. ; Schlepckow, K.DZNE* ; Degan, S. ; Chew, L. ; Amason, J. ; Kalnitsky, J. ; Bowes Rickman, C. ; Proia, A. D. ; Colonna, M. ; Haass, C.DZNE* ; Saban, D. R.

2024
Rockefeller Univ. Press New York, NY

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Please use a persistent id in citations: doi:10.1084/jem.20231011

Abstract: 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.

Keyword(s): Aged (MeSH) ; Animals (MeSH) ; Mice (MeSH) ; Humans (MeSH) ; Galectin 3: genetics (MeSH) ; Retinal Degeneration (MeSH) ; Microglia (MeSH) ; Macrophages (MeSH) ; Atrophy (MeSH) ; Membrane Glycoproteins: genetics (MeSH) ; Receptors, Immunologic: genetics (MeSH) ; Lgals3 protein, mouse ; Galectin 3 ; Trem2 protein, mouse ; Membrane Glycoproteins ; Receptors, Immunologic

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Contributing Institute(s):

1. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Essential Science Indicators ; IF >= 15 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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