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

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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. Significance Recent evidence suggests human retinal Müller glia retain a potential for neuronal regeneration. Defining the mechanisms governing retinal repair in robustly regenerative species may provide insights for harnessing this potential therapeutically. Here, we investigated roles of the innate immune system during rod photoreceptor regeneration in zebrafish. Our data establish a role for retinal microglia, the tissue-resident macrophage of the retina, in regulating retinal Müller glia responsiveness to cell death, and thereby controlling photoreceptor regeneration kinetics. Further, we show that immunosuppression can either inhibit or accelerate photoreceptor regeneration kinetics depending on the timing of treatment. We conclude that modulation of immune cell responses to retinal neuron cell death stands as a promising strategy for promoting repair of the human eye.
Funding Information
  • HHS | NIH | National Eye Institute (EY022810)
  • HHS | NIH | National Center for Advancing Translational Sciences (R41TR000945)

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