Nanoparticle-based targeting of microglia improves the neural regeneration enhancing effects of immunosuppression in the zebrafish retina

Analysing microglial activity in a zebrafish model of photoreceptor degeneration shows the immunosuppressive effect of dexamethasone in vivo and that dexamethasone conjugation to dendrimer nanoparticles greatly enhances photoreceptor regeneration. Retinal Muller glia function as injury-induced stem-like cells in zebrafish but not mammals. However, insights gleaned from zebrafish have been applied to stimulate nascent regenerative responses in the mammalian retina. For instance, microglia/macrophages regulate Muller glia stem cell activity in the chick, zebrafish, and mouse. We previously showed that post-injury immunosuppression by the glucocorticoid dexamethasone accelerated retinal regeneration kinetics in zebrafish. Similarly, microglia ablation enhances regenerative outcomes in the mouse retina. Targeted immunomodulation of microglia reactivity may therefore enhance the regenerative potential of Muller glia for therapeutic purposes. Here, we investigated potential mechanisms by which post-injury dexamethasone accelerates retinal regeneration kinetics, and the effects of dendrimer-based targeting of dexamethasone to reactive microglia. Intravital time-lapse imaging revealed that post-injury dexamethasone inhibited microglia reactivity. The dendrimer-conjugated formulation: (1) decreased dexamethasone-associated systemic toxicity, (2) targeted dexamethasone to reactive microglia, and (3) improved the regeneration enhancing effects of immunosuppression by increasing stem/progenitor proliferation rates. Lastly, we show that the gene rnf2 is required for the enhanced regeneration effect of D-Dex. These data support the use of dendrimer-based targeting of reactive immune cells to reduce toxicity and enhance the regeneration promoting effects of immunosuppressants in the retina.

Automated summary

Analyzing microglial activity in a zebrafish model, the study shows the immunosuppressive effect of dexamethasone in vivo and the enhanced photoreceptor regeneration when conjugated to dendrimer nanoparticles. The study also discusses the potential mechanisms by which dexamethasone accelerates retinal regeneration and the effects of dendrimer-based targeting. Intravital time-lapse imaging revealed that post-injury dexamethasone inhibited microglia reactivity, and the dendrimer-conjugated formulation decreased toxicity and improved regeneration enhancing effects.