Photoreceptor regeneration occurs normally in microglia-deficient irf8 mutant zebrafish following acute retinal damage

Sci Rep. 2024 Aug 30;14(1):20146. doi: 10.1038/s41598-024-70859-9.

Abstract

Microglia are resident immune cells in the central nervous system, including the retina that surveil the environment for damage and infection. Following retinal damage, microglia undergo morphological changes, migrate to the site of damage, and express and secrete pro-inflammatory signals. In the zebrafish retina, inflammation induces the reprogramming and proliferation of Müller glia and the regeneration of neurons following damage or injury. Immunosuppression or pharmacological ablation of microglia reduce or abolish Müller glia proliferation. We evaluated the retinal architecture and retinal regeneration in adult zebrafish irf8 mutants, which have significantly depleted numbers of microglia. We show that irf8 mutants have normal retinal structure at 3 months post fertilization (mpf) and 6 mpf but fewer cone photoreceptors by 10 mpf. Surprisingly, light-induced photoreceptor ablation induced Müller glia proliferation in irf8 mutants and cone and rod photoreceptor regeneration. Light-damaged retinas from both wild-type and irf8 mutants show upregulated expression of mmp-9, il8, and tnfβ pro-inflammatory cytokines. Our data demonstrate that adult zebrafish irf8 mutants can regenerate normally following acute retinal injury. These findings suggest that microglia may not be essential for retinal regeneration in zebrafish and that other mechanisms can compensate for the reduction in microglia numbers.

Keywords: Inflammation; Microglia; Müller glia; Photoreceptors; Regeneration; Retina.

MeSH terms

  • Animals
  • Cell Proliferation
  • Ependymoglial Cells / metabolism
  • Ependymoglial Cells / pathology
  • Interferon Regulatory Factors* / genetics
  • Interferon Regulatory Factors* / metabolism
  • Light
  • Microglia* / metabolism
  • Mutation
  • Photoreceptor Cells, Vertebrate / metabolism
  • Photoreceptor Cells, Vertebrate / pathology
  • Regeneration
  • Retina* / metabolism
  • Retina* / pathology
  • Retinal Cone Photoreceptor Cells / metabolism
  • Retinal Cone Photoreceptor Cells / pathology
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism
  • Zebrafish*

Substances

  • Interferon Regulatory Factors
  • interferon regulatory factor-8
  • Zebrafish Proteins