Genetic targeting or pharmacological inhibition of galectin-3 dampens microglia reactivity and delays retinal degeneration.

Abstract

BACKGROUND:

Dysfunctional humoral and cellular innate immunity are key components in the development and progression of age-related macular degeneration (AMD). Specifically, chronically activated microglia and their disturbed regulatory system contribute to retinal degeneration. Galectin-3, a β-galactose binding protein, is a potent driver of macrophage and microglia activation and has been implicated in neuroinflammation, including neurodegenerative diseases of the brain. Here, we hypothesized that genetic deficiency of galectin-3 or its modulation via TD139 dampens mononuclear phagocyte reactivity and delays retinal degeneration.

METHODS:

Galectin-3 expression in AMD patients was analyzed by immunohistochemical stainings. Galectin-3 knockout and BALB/cJ mice were exposed to white bright light with an intensity of 15,000 lux for 1 h and Cx3cr1GFP/+ mice to focal blue light of 50,000 lux for 10 min. BALB/cJ and Cx3cr1GFP/+ mice received intraperitoneal injections of 15 mg/kg TD139 or vehicle for five consecutive days, starting one day prior to light exposure. The effects of galectin-3 deficiency or inhibition on microglia were analyzed by immunohistochemical stainings and in situ hybridization of retinal sections and flat mounts. Pro-inflammatory cytokine levels in the retina and retinal pigment epithelium (RPE) were quantified by qRT-PCR and transcriptomic changes were analyzed by RNA-sequencing. Retinal thickness and structure were evaluated by optical coherence tomography.

RESULTS:

We found that galectin-3 expression was strongly upregulated in reactive retinal mononuclear phagocytes of AMD patients and in the two related mouse models of light-induced retinal degeneration. The experimental in vivo data further showed that specific targeting of galectin-3 by genetic knockout or administration of the small-molecule inhibitor TD139 reduced microglia reactivity and delayed retinal damage in both light damage conditions.

CONCLUSION:

This study defines galectin-3 as a potent driver of retinal degeneration and highlights the protein as a drug target for ocular immunomodulatory therapies.

• Authors: Mona Tabel, Anne Wolf, Manon Szczepan, Heping Xu, Herbert Jägle, Christoph Moehle, Mei Chen, Thomas Langmann
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 19 Issue 1 Pg. 229 (Sep 17 2022) ISSN: 1742-2094 [Electronic] England
• PMID: 36115971 (Publication Type: Journal Article)
• Copyright: © 2022. The Author(s).

Chemical References

• Cytokines
• Galectin 3
• Lgals3 protein, mouse
• Thiogalactosides
• Triazoles
• GB-0139
• RNA

Topics

• Animals
• Cytokines (metabolism)
• Galectin 3 (antagonists & inhibitors, genetics, metabolism)
• Humans
• Macular Degeneration (genetics, metabolism, prevention & control)
• Mice
• Microglia (metabolism)
• Monocytes (drug effects, metabolism)
• RNA (metabolism)
• Retina (drug effects, metabolism)
• Retinal Degeneration (genetics, metabolism, prevention & control)
• Thiogalactosides (pharmacology)
• Triazoles (pharmacology)