Context-Dependent Effects of Inflammation On Retina Regeneration

Abstract Inflammation is required for the proliferation of Müller glia (MG) into multipotent progenitors (MGPCs) in the injured fish and avian retinas. However, its function in retina regeneration has not been fully understood. Here we investigated the role of inflammation in three different retinal regeneration paradigms in zebrafish (stab-injury, NMDA-injury and insulin treatment). We first show that different types of immune cells and levels of inflammatory cytokines were found in the retinas of these paradigms. Though zymosan injection alone was insufficient to induce MG proliferation in the uninjured retina, immune suppression significantly inhibited MGPC formation in all three paradigms. Enhancing inflammation promoted MGPC formation after stab-injury, while exhibiting a context-dependent role in the NMDA or insulin models. Furthermore, proper levels of inflammation promoted MG reprogramming and cell cycle re-entry after stab- or NMDA-injury, but excessive inflammation also suppressed MG proliferation in the latter model. Finally, while inflammation promoted retinal neuron regeneration after stab-injury, immune suppression surprisingly achieved the best regeneration in the NMDA model. Our study reveals the complex and context-dependent role of inflammation during retinal repair in fish, and suggests accurate inflammation management may be crucial for successful retina regeneration in mammals.