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.

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.

MeSH terms

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

Substances

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