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

Kevin Emmerich; David T White; Siva P Kambhampati; Grace L Casado; Tian-Ming Fu; Zeeshaan Chunawala; Arpan Sahoo; Saumya Nimmagadda; Nimisha Krishnan; Meera T Saxena; Steven L Walker; Eric Betzig; Rangaramanujam M Kannan; Jeff S Mumm

doi:10.1038/s42003-023-04898-9

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

Commun Biol. 2023 May 18;6(1):534. doi: 10.1038/s42003-023-04898-9.

Authors

Kevin Emmerich^#^{1

2}, David T White^#², Siva P Kambhampati^#^{2

3}, Grace L Casado², Tian-Ming Fu^{4

5}, Zeeshaan Chunawala², Arpan Sahoo², Saumya Nimmagadda², Nimisha Krishnan², Meera T Saxena², Steven L Walker⁶, Eric Betzig⁷, Rangaramanujam M Kannan^{8

9}, Jeff S Mumm^{10

11

12

13}

Affiliations

¹ McKusick-Nathans Institute of the Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
² Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA.
³ The Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA.
⁴ Janelia Farms Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA.
⁵ Department of Electrical and Computer Engineering and Princeton Bioengineering Initiative, Princeton University, Princeton, NJ, USA.
⁶ School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
⁷ Janelia Farms Research Campus, Howard Hughes Medical Institute, Ashburn, VA, USA. betzige@janelia.hhmi.org.
⁸ Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA. krangar1@jhmi.edu.
⁹ The Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA. krangar1@jhmi.edu.
¹⁰ McKusick-Nathans Institute of the Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. jmumm3@jhmi.edu.
¹¹ Department of Ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA. jmumm3@jhmi.edu.
¹² The Center for Nanomedicine, Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD, USA. jmumm3@jhmi.edu.
¹³ Solomon H Snyder Department of Neuroscience, Johns Hopkins University, Baltimore, MD, USA. jmumm3@jhmi.edu.

^# Contributed equally.

Abstract

Retinal Müller 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 Müller 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 Müller 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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Dendrimers* / pharmacology
Dexamethasone / pharmacology
Immunosuppression Therapy
Mammals
Mice
Microglia
Retina / physiology
Zebrafish*

Substances

Dendrimers
Dexamethasone

Abstract

Publication types

MeSH terms

Substances

Grants and funding