September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Inflammation, MMP9 expression, and photoreceptor regeneration in the adult zebrafish retina
Author Affiliations & Notes
  • Nicholas Jeremy Silva
    Neuroscience, University of Michigan, Ann Arbor, Michigan, United States
    Ophthalmology & Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
  • Jingling Li
    Biological Science, University of Notre Dame, Notre Dame, Indiana, United States
  • David R Hyde
    Biological Science, University of Notre Dame, Notre Dame, Indiana, United States
  • Peter F Hitchcock
    Ophthalmology & Visual Sciences, University of Michigan, Ann Arbor, Michigan, United States
    Neuroscience, University of Michigan, Ann Arbor, Michigan, United States
  • Footnotes
    Commercial Relationships   Nicholas Silva, None; Jingling Li, None; David Hyde, None; Peter Hitchcock, None
  • Footnotes
    Support  T32- NIH Vision Research Training Program (VRTP)
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 577. doi:
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    • Get Citation

      Nicholas Jeremy Silva, Jingling Li, David R Hyde, Peter F Hitchcock; Inflammation, MMP9 expression, and photoreceptor regeneration in the adult zebrafish retina. Invest. Ophthalmol. Vis. Sci. 2016;57(12):577.

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

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Abstract

Purpose : Inflammation resulting from injury to the central nervous system (CNS) activates a multifaceted network of signaling molecules. Previously, inflammation was thought to be detrimental to CNS regeneration. However, recent studies suggest that inflammation is necessary to initiate neuronal repair and regeneration after injury. The purpose of this study was to use the adult zebrafish retina to (1) determine if inflammation regulates stem cell-based photoreceptor regeneration, and (2) investigate the expression of MMP9 as a component of the inflammatory response.

Methods : Fish were treated with dexamethasone (DEX) to suppress the immune response prior to the onset of a photolytic lesion and sacrificed at 3 or 7 days post lesion (dpl). 24 hrs prior to sacrifice, mitotic cells were labeled with BrdU. Eyecups and retinal RNA were collected for immunochemistry and qPCR analysis, respectively. BrdU+ cells were counted at 3 dpl, and photoreceptor regeneration was evaluated by qPCR at 7 dpl. In addition, the expression of mmp9 was evaluated by in situ hybridization and qPCR in animals that were subjected to a photolytic lesion and sacrificed at 16, 24, 48, and 72 hpl. To mimic inflammation, we intravitreally injected TNF-α and measured mmp9 expression by qPCR.

Results : Gene expression analysis of the inflammatory molecules, tnf-α, tnf-β, IL-1β, Clcf1, and mmp9 were used to validate the immunosuppression. Relative to controls, the expression of all genes, except tnf-α, decreased following DEX treatment. Additionally, compared to controls, immunosuppression reduced the number of injury-induced BrdU+ progenitors by nearly half. Immunosuppression also diminished rod photoreceptor regeneration. At 7 dpl, rhodopsin expression was significantly decreased, whereas the expression of pde6c (cones) matched controls. At 16 and 24 hpl, photoreceptor injury and death significantly upregulated mmp9, which was expressed in mitotic Müller glia and photoreceptor progenitors. Interestingly, in uninjured retinas, intravitreal injections of the pro-inflammatory cytokine, TNF-α, dramatically induced mmp9 expression.

Conclusions : Our results demonstrate that inflammation following photoreceptor injury and death regulates proliferation of stem and progenitor cells and governs the regeneration of rod photoreceptors. Our data also shows that MMP9 is a component of TNF-α signaling from dying photoreceptors to Müller glia.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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