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

  • J Neuroinflammation. 2022 Sep 17;19(1):229. doi: 10.1186/s12974-022-02589-6.
Mona Tabel  1 ,  Anne Wolf  1 ,  Manon Szczepan  2 ,  Heping Xu  2 ,  Herbert Jägle  3 ,  Christoph Moehle  4 ,  Mei Chen  #  2 ,  Thomas Langmann  #  5  6
Affiliations
  • 1. Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
  • 2. Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
  • 3. Department of Ophthalmology, University Eye Clinic Regensburg, Regensburg, Germany.
  • 4. Center of Excellence for Fluorescent Bioanalytics, University of Regensburg, Regensburg, Germany.
  • 5. Laboratory for Experimental Immunology of the Eye, Department of Ophthalmology, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany. [email protected].
  • 6. Centre for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. [email protected].
  • # Contributed equally.
PMID: 36115971 DOI: 10.1186/s12974-022-02589-6
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.

Keywords
Galectin-3 deficiency; Galectin-3 inhibition; Light damage; Microglia; Retinal degeneration; TD139.
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