PUBLICATION

Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina

Authors
White, D.T., Sengupta, S., Saxena, M.T., Xu, Q., Hanes, J., Ding, D., Ji, H., Mumm, J.S.
ID
ZDB-PUB-170419-5
Date
2017
Source
Proceedings of the National Academy of Sciences of the United States of America   114(18): E3719-E3728 (Journal)
Registered Authors
Mumm, Jeff, Saxena, Meera T., White, David T.
Keywords
glucocorticoid, macrophage, microglia, regeneration, retina
MeSH Terms
  • Ependymoglial Cells/immunology*
  • Ependymoglial Cells/pathology
  • Humans
  • Immunomodulation*
  • Immunity, Innate*
  • Animals
  • Retinal Rod Photoreceptor Cells/pathology
  • Retinal Rod Photoreceptor Cells/physiology*
  • Regeneration/immunology*
  • Zebrafish/immunology*
(all 10)
PubMed
28416692 Full text @ Proc. Natl. Acad. Sci. USA
Abstract
Müller glia (MG) function as inducible retinal stem cells in zebrafish, completely repairing the eye after damage. The innate immune system has recently been shown to promote tissue regeneration in which classic wound-healing responses predominate. However, regulatory roles for leukocytes during cellular regeneration-i.e., selective cell-loss paradigms akin to degenerative disease-are less well defined. To investigate possible roles innate immune cells play during retinal cell regeneration, we used intravital microscopy to visualize neutrophil, macrophage, and retinal microglia responses to induced rod photoreceptor apoptosis. Neutrophils displayed no reactivity to rod cell loss. Peripheral macrophage cells responded to rod cell loss, as evidenced by morphological transitions and increased migration, but did not enter the retina. Retinal microglia displayed multiple hallmarks of immune cell activation: increased migration, translocation to the photoreceptor cell layer, proliferation, and phagocytosis of dying cells. To test function during rod cell regeneration, we coablated microglia and rod cells or applied immune suppression and quantified the kinetics of (i) rod cell clearance, (ii) MG/progenitor cell proliferation, and (iii) rod cell replacement. Coablation and immune suppressants applied before cell loss caused delays in MG/progenitor proliferation rates and slowed the rate of rod cell replacement. Conversely, immune suppressants applied after cell loss had been initiated led to accelerated photoreceptor regeneration kinetics, possibly by promoting rapid resolution of an acute immune response. Our findings suggest that microglia control MG responsiveness to photoreceptor loss and support the development of immune-targeted therapeutic strategies for reversing cell loss associated with degenerative retinal conditions.
Genes / Markers
Figures
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Expression
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
a9
    		Complex
    gmc500TgTransgenic Insertion
      mi2001TgTransgenic Insertion
        uwm1TgTransgenic Insertion
          w201TgTransgenic Insertion
            w202TgTransgenic Insertion
              1 - 6 of 6
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              Human Disease / Model
              No data available
              Sequence Targeting Reagents
              No data available
              Fish
              No data available
              Antibodies
              Orthology
              No data available
              Engineered Foreign Genes
              Marker Marker Type Name
              CeruleanEFGCerulean
              EYFPEFGEYFP
              GFPEFGGFP
              NTREFGNTR
              TomatoEFGTomato
              YFPEFGYFP
              1 - 6 of 6
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              Mapping
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              Citation
              White, D.T., Sengupta, S., Saxena, M.T., Xu, Q., Hanes, J., Ding, D., Ji, H., Mumm, J.S. (2017) Immunomodulation-accelerated neuronal regeneration following selective rod photoreceptor cell ablation in the zebrafish retina. Proceedings of the National Academy of Sciences of the United States of America. 114(18):E3719-E3728.