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Oliver Bludau, Veronika Kuscha, Anke Weber, Michael Brand; Neuroinflammation is critically required as a regenerative cue of the adult zebrafish retina. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4597. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Chronic inflammatory retinal diseases often cause neuronal loss in mammalian vertebrates. These diseases are marked by leakage of blood vessels, leukocyte infiltration and gliosis, leading to persistent and so far irreversible loss of retinal neurons and photoreceptors. In contrast to mammals, neuronal inflammation in zebrafish is crucially important and sufficient to stimulate a regenerative response after traumatic brain injury. Here we have tested the hypothesis that the immune system contributes to adult retina regeneration in zebrafish.
Leukocyte activation upon photoreceptor ablation was monitored using immunohistochemistry and transgenic reporter lines labelling markers for macrophages, neutrophils and T-cells. Further, to investigate the role of the immune system during retina regeneration, we performed immunosuppression using dexamethasone in combination with sterile photoreceptor ablation. Immunosuppressed fish were analysed for the numbers of leucocytes, proliferating Müller glia cells, as well as the overall number of proliferating cells. To elucidate whether stimulation of the immune system in the absence of lesion is sufficient to induce a regenerative response, we performed intravitreal injections of zymosan and flagellin. These retinae were then analysed for proliferation and expression of regeneration marker genes.
Several results show an activation of the immune system after light lesion such as significant accumulation of leukocytes at the lesion site, recruitment of neutrophils and morphological changes of microglia. However, we do not observe T-cell accumulation at the lesion site. Under immunosuppression, we observe a lower activation of the immune cells, significant reduction of cycling Müller glia as well as a striking decrease of overall proliferation. Furthermore, Müller glia cells also show an impaired transcpritional response, e.g. a lack mmp9 expression, a marker we found to be expressed by Müller glia. Conversely, immune stimulation in the absence of lesion resulted in a robust proliferative response and the up-regulation of regenerative marker genes in clusters of neuronal precursor cells.
We conclude that neuronal inflammation occurs in the zebrafish retina following photoreceptor ablation. Moreover, we show that acute neuronal inflammation is essential to initiate successful regeneration of photoreceptors.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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