June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Dendrimer-targeted immunosuppression of microglia reactivity super-accelerates photoreceptor regeneration kinetics in the zebrafish retina
Author Affiliations & Notes
  • Kevin Emmerich
    1. McKusick-Nathans Institute of the Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
    2. Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • David T White
    2. Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Siva P Kambhampati
    2. Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
    The Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Grace Y Lee
    2. Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Tian-Ming Fu
    Howard Hughes Medical Institute - Janelia Farm Research Campus, Ashburn, Virginia, United States
  • Arpan Sahoo
    2. Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Meera T Saxena
    2. Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Eric Betzig
    Howard Hughes Medical Institute - Janelia Farm Research Campus, Ashburn, Virginia, United States
  • Rangaramanujam M Kannan
    2. Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
    The Center for Nanomedicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Jeff S Mumm
    1. McKusick-Nathans Institute of the Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
    2. Department of Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
  • Footnotes
    Commercial Relationships   Kevin Emmerich, None; David White, None; Siva Kambhampati, None; Grace Lee, None; Tian-Ming Fu, None; Arpan Sahoo, None; Meera Saxena, None; Eric Betzig, None; Rangaramanujam Kannan, Ashvattha Therapeutics Inc (P), Ashvattha Therapeutics Inc (I); Jeff Mumm, Washington University (P)
  • Footnotes
    Support  R01OD020376, NIH/NEI-R01EY025304
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 2243. doi:
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    • Get Citation

      Kevin Emmerich, David T White, Siva P Kambhampati, Grace Y Lee, Tian-Ming Fu, Arpan Sahoo, Meera T Saxena, Eric Betzig, Rangaramanujam M Kannan, Jeff S Mumm; Dendrimer-targeted immunosuppression of microglia reactivity super-accelerates photoreceptor regeneration kinetics in the zebrafish retina. Invest. Ophthalmol. Vis. Sci. 2021;62(8):2243.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : We previously showed that microglia are key regulators of retinal regeneration in zebrafish. Microglia reactivity to induced rod photoreceptor death stimulates Müller glia to mount a regenerative response. Ablating microglia or suppressing microglia reactivity with dexamethasone (Dex) prior to induction of cell death inhibited regeneration. However, suppressing microglia reactivity after induction of rod death enhanced regeneration kinetics. These data support the concept that microglia play stage-dependent roles during retinal regeneration and that immunosuppression could be a viable therapeutic approach for promoting repair in retinal degenerative disease. Here, we used intravital time-lapse imaging to investigate how post-injury Dex treatment altered microglia reactivity. We also tested what effect targeted delivery of Dex to reactive immune cells following induction of rod cell death had on regeneration kinetics.

Methods : Metronidazole (Mtz) induced rod cell death was enabled by a transgenic line expressing bacterial nitroreductase (NTR) and a fluorescent reporter in rod photoreceptors. A novel intravital imaging technique, Adaptive Optics-Lattice Light Sheet Microscopy (AO-LLSM), was used to capture fast subcellular dynamics of microglia. Imaris was used to quantify aspects of microglia behavior during regeneration ± Dex. Dendrimer conjugated Dex (Dendrimer-Dex) was evaluated for effects on rod cell regeneration kinetics using an established plate reader assay.

Results : AO-LLSM time-lapse imaging showed that post-injury Dex represses reactivity to rod cell death by reducing the speed of microglia migration rather than altering morphology (sphericity). Compared to free Dex controls, Dendrimer-Dex formulations led to: 1) reduced toxicity, 2) targeted delivery of Dex to reactive microglia, and 3) a further enhancement of regeneration kinetics, from +33% (free Dex controls) to +67% (Dendrimer-Dex treated fish).

Conclusions : These results increase our understanding of the roles microglia play during retinal regeneration and advance the therapeutic potential of immune suppressing drugs and dendrimer-based immune cell targeting in retinal disease settings.

This is a 2021 ARVO Annual Meeting abstract.

 

Figure. Microglia migration speed is suppressed in response to post-ablation Dex treatment. Each dot in E+F represents one fish.

Figure. Microglia migration speed is suppressed in response to post-ablation Dex treatment. Each dot in E+F represents one fish.

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