Tabel, Mona and Wolf, Anne and Szczepan, Manon and Xu, Heping and Jaegle, Herbert and Moehle, Christoph and Chen, Mei and Langmann, Thomas (2022) Genetic targeting or pharmacological inhibition of galectin-3 dampens microglia reactivity and delays retinal degeneration. JOURNAL OF NEUROINFLAMMATION, 19 (1): 229. ISSN , 1742-2094
Full text not available from this repository. (Request a copy)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 beta-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 Cx3cr1(GFP/+) mice to focal blue light of 50,000 lux for 10 min. BALB/cJ and Cx3cr1(GFP/+) 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MACULAR DEGENERATION; LUNG FIBROSIS; ACTIVATION; IMPAIRMENT; CELLS; Galectin-3 deficiency; Galectin-3 inhibition; TD139; Microglia; Retinal degeneration; Light damage |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Augenheilkunde |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 22 Feb 2024 15:19 |
| Last Modified: | 22 Feb 2024 15:19 |
| URI: | https://pred.uni-regensburg.de/id/eprint/57779 |
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