July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
Inhibition of microglia cells delays retinal degeneration in experimental branch retinal vein occlusion in mice
Author Affiliations & Notes
  • Joel Jovanovic
    Ophthalmology, Inselspital, Bern University Hospital, Bern, Switzerland
    Department of BioMedical Research, DBMR, University of Bern, Bern, Switzerland
  • Despina Kokona
    Ophthalmology, Inselspital, Bern University Hospital, Bern, Switzerland
    Department of BioMedical Research, DBMR, University of Bern, Bern, Switzerland
  • Andreas Ebneter
    Ophthalmology, Inselspital, Bern University Hospital, Bern, Switzerland
    Department of BioMedical Research, DBMR, University of Bern, Bern, Switzerland
  • Martin Sebastian Zinkernagel
    Ophthalmology, Inselspital, Bern University Hospital, Bern, Switzerland
    Department of BioMedical Research, DBMR, University of Bern, Bern, Switzerland
  • Footnotes
    Commercial Relationships   Joel Jovanovic, None; Despina Kokona, Bayer (F); Andreas Ebneter, Allergan (C), Allergan (F), Bayer (R), Novartis (F), Novartis (R); Martin Zinkernagel, Allergan (F), Bayer (F), Bayer (C), Heidelberg Engineering (F), Novartis (I), Novartis (C)
  • Footnotes
    Support  Inselgrant 84800858
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 3994. doi:https://doi.org/
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    • Get Citation

      Joel Jovanovic, Despina Kokona, Andreas Ebneter, Martin Sebastian Zinkernagel; Inhibition of microglia cells delays retinal degeneration in experimental branch retinal vein occlusion in mice. Invest. Ophthalmol. Vis. Sci. 2019;60(9):3994. doi: https://doi.org/.

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

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Abstract

Purpose : Branch retinal vein occlusion (BRVO) is a frequent cause of vision loss, primarily affecting retinal ganglion cells (RGC) and the retinal nerve fiber layer. Experimental branch retinal vein occlusion (eBRVO) in mice mimics inner retina layer ischemia in humans and leads to activated microglia in the hypoxic area. We hypothesize that suppression of retinal microglia exhibits protective effects on RGC survival after ischemic eBRVO in mice.

Methods : Microglia cells were pharmacologically depleted by PLX5622, a specific small molecule inhibitor for the CSF-1 receptor (CSF1R) expressed on microglia/macrophages in the CNS. Cx3cr1gfp/+ mice, specifically expressing green fluorescent protein (GFP) in microglia/macrophages, were fed with PLX5622 chow for two weeks before laser-induced eBRVO. One group of mice was continuously treated with PLX5622 for three more weeks, while a second group was switched to normal diet directly after BRVO induction (microglia recovery group). A third group only underwent laser-induced eBRVO, without any PLX5622-treatment (non-PLX5622 treated group). Depletion and changes in activation were observed in vivo by blue laser scanning laser ophthalmoscopy. Histology assessments included immunohistochemistry for Brn3a (retinal ganglion cells) and Iba1 (microglia/macrophages) on whole mounted retinas. OCT scans were performed to assess retinal thickness.

Results : PLX5622 caused dramatic suppression of microglia. In continuously depleted mice, RGC survival was improved by 45% compared to the non-PLX5622 treated group at the three weeks time point. Reappearance of GFP-positive cells was almost entirely absent with continuous treatment and significantly delayed after cessation, in particular in ischemic tissue. In addition, OCT scans showed a delay of retinal atrophy in microglia depleted mice.

Conclusions : Findings suggest that elimination of cells bearing the colony-stimulating factor-1 receptor, mainly microglia and invading monocytes, mitigates hypoxic damage and salvages RGCs. Protective effects seem primarily be rooted in processes around blood-retina barrier breakdown. Modulation of microglia in ischemic retinal disease might represent a novel therapeutic approach.

This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.

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