Investigating the Role of Microglia in Retinal Regeneration of the Adult Zebrafish Retina

The zebrafish possesses a remarkable ability to regenerate dying retinal neurons in response to retinal injury. Both microglia and Müller glia play integral roles in this regenerative process. Resident Müller glia respond to damage by reprogramming and undergoing asymmetric cell division to generate neuronal progenitor cells. These progenitor cells continue to proliferate and differentiate into the lost neurons. In contrast, microglia become reactive, phagocytose dying cells, and release inflammatory signals into the surrounding tissue following damage. In recent years, there has been heightened attention in elucidating the intricate interplay between retinal regeneration and the immune system. Here I demonstrate that microglia become reactive and phagocytose dying photoreceptors following light damage. I also show that chemokines and inflammatory cytokines are differentially expressed during retinal regeneration, where the expression of a subset of pro-inflammatory cytokine genes is upregulated shortly after light damage and the expression of a subset of anti-inflammatory cytokine
genes is delayed before increasing their expression. Both pro-inflammatory cytokine IL- 1ß and anti-inflammatory cytokine IL-10 are essential for Müller glia proliferation in the light-damaged retinas. The absence of either IL-1ß or IL-10 results in fewer PCNA+ Müller glia in the damaged retinas. However, IL-1ß is sufficient to induce Müller glia proliferation in the undamaged retinas. While IL-10 is unable to induce Müller glia proliferation in undamaged retinas, it induces the Müller glia to adopt a gliotic cell morphology and expression of several gliotic genes. Together, these findings demonstrate the essential role of inflammatory cytokines IL-1ß and IL-10 in regeneration in the adult zebrafish retina.

斑马鱼（zebrafish）具备卓越的损伤响应能力，可再生因视网膜损伤而凋亡的视网膜神经元。小胶质细胞（microglia）与米勒胶质细胞（Müller glia）在这一再生过程中均发挥不可或缺的核心作用。驻留的米勒胶质细胞会通过重编程并进行不对称细胞分裂，产生神经元祖细胞（neuronal progenitor cells）以响应损伤。这些祖细胞会持续增殖并分化为缺失的神经元。与之相对，小胶质细胞会在损伤后被激活，吞噬凋亡细胞，并向周围组织释放炎症信号。近年来，学界对解析视网膜再生与免疫系统间复杂的相互作用给予了高度关注。本研究证实，在光损伤后，小胶质细胞会被激活并吞噬凋亡的感光细胞（photoreceptors）。同时本研究还发现，趋化因子（chemokines）与炎症细胞因子（inflammatory cytokines）在视网膜再生过程中呈差异性表达：部分促炎细胞因子基因的表达会在光损伤后短期内上调，而另一部分抗炎细胞因子基因的表达则会先出现延迟，随后才会上调。促炎细胞因子白细胞介素-1β（IL-1ß）与抗炎细胞因子白细胞介素-10（IL-10）均对光损伤视网膜中的米勒胶质细胞增殖至关重要。若缺失IL-1ß或IL-10，损伤视网膜内增殖细胞核抗原阳性（PCNA+）的米勒胶质细胞数量会显著减少。不过，IL-1ß足以在未受损伤的视网膜中诱导米勒胶质细胞增殖。尽管IL-10无法在未损伤的视网膜中诱导米勒胶质细胞增殖，但它可促使米勒胶质细胞呈现胶质增生（gliotic）的细胞形态，并上调多种胶质增生相关基因的表达。综上，本研究结果证实了炎症细胞因子IL-1ß与IL-10在成年斑马鱼视网膜再生过程中的关键作用。