Abstract
Purpose :
Unlike mammals, zebrafish regenerate in response to retinal damage. Because microglia are activated by retinal damage, we investigated their role during regeneration following acute or chronic damage. How inflammation regulates regeneration in zebrafish would provide important clues towards improving the therapeutic strategies for repairing injured mammalian tissues.
Methods :
We used three weeks-post-fertilization (wpf) zebrafish exhibiting either NMDA-induced acute retinal damage or chronic retinal damage due to the cone photoreceptor-specific degeneration mutation gold rush (gosh). Fishes were treated with either dexamethasone to inhibit the immune response or LPS to stimulate the immune response. Immunohistochemistry and transgenic lines were used to monitor the proliferative response and microglia. Pro-inflammatory and anti-inflammatory cytokines were tested by qRT-PCR.
Results :
NMDA-induced acute damage or the gosh chronic degeneration mutant displayed reactive microglia and Muuller glia proliferation. Retinas treated to inhibit the immune response lacked reactive microglia and possessed fewer PCNA-positive cells, while LPS treatment increased microglia and PCNA-labeled cells. NMDA-injured retinas upregulated the expression of IL-1β and TNF-α pro-inflammatory cytokine genes, followed by increased expression of IL-10 and Arg1 anti-inflammatory/remodeling cytokine genes. An early and transient TNF-α pro-inflammatory microglia population was identified following acute damage. In contrast, gosh mutant retinas exhibited a mild increase of pro-inflammatory cytokine gene expression concurrent with a major anti-inflammatory/remodeling cytokine gene expression. Few TNF-α pro-inflammatory microglia were observed in the gosh retina.
Conclusions :
Acute or chronic retinal damage induces an immune response that modulates the proliferative response in zebrafish larvae. However, acute and chronic damage display different immunological response strategies. While acute damage presents an early and transient proinflammatory response, chronic damage presents a weak pro-inflammatory and a strong anti-inflammatory response simultaneously.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.