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Microglia mediate non-cell-autonomous cell death of retinal ganglion cells

Akiko Takeda1, Youichi Shinozaki1, Kenji Kashiwagi2

  • 1Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.

Glia
|October 31, 2018
PubMed

Insights

Microglia mediate retinal excitotoxicity by releasing tumor necrosis factor α (TNFα), leading to retinal ganglion cell (RGC) death. Inhibiting microglia or TNFα protects RGCs, highlighting a non-cell-autonomous mechanism in retinal damage.

Area of Science:

  • Neuroscience
  • Ophthalmology
  • Immunology

Background:

  • Excitotoxicity is a known cause of neuronal death in the brain and retina.
  • Microglia's role in brain excitotoxicity is established, but their function in retinal excitotoxicity is less understood.
  • Retinal ganglion cells (RGCs) are vulnerable to excitotoxic damage.

Purpose of the Study:

  • To investigate the role of microglia in mediating excitotoxicity in the retina.
  • To determine the specific mechanisms by which microglia contribute to RGC damage.
  • To explore potential therapeutic targets for preventing retinal excitotoxicity.

Main Methods:

  • Pharmacological inhibition of microglia using minocycline.
  • Pharmacological ablation of microglia using a colony stimulating factor 1 receptor antagonist (PLX5622).
  • Genetic ablation of microglia in Iba1-tTA::DTAtetO/tetO mice.
  • Intravitreal NMDA injection to induce excitotoxicity.
  • Analysis of RGC apoptosis and survival.
  • Measurement of proinflammatory cytokine gene expression (Il1b, Il6, Tnfa).
  • Assessment of TNFα signaling pathways.
  • Inhibition of TNFα and knockdown of TNF receptor type 1 (TNFR1).

Main Results:

  • NMDA injection induced RGC apoptosis and loss.
  • Microglia became reactive prior to RGC damage and mediated excitotoxicity.
  • Inhibition or ablation of microglia protected RGCs from NMDA-induced damage.
  • Microglia up-regulated proinflammatory cytokines, particularly TNFα.
  • Minocycline and PLX5622 suppressed TNFα expression and signaling.
  • Inhibition of TNFα or TNFR1 also protected RGCs against NMDA toxicity.

Conclusions:

  • Microglia play a critical role in mediating NMDA-induced retinal excitotoxicity.
  • Microglia adopt a neurotoxic phenotype, contributing to RGC degeneration via TNFα.
  • Non-cell-autonomous mechanisms involving microglia are crucial in retinal neuronal excitotoxicity.
Keywords:
cytokinesexcitotoxicitymicrogliaretinal ganglion cellstumor necrosis factor

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