Disease-associated microglial activation prevents photoreceptor degeneration by suppressing the accumulation of cell debris and neutrophils in degenerating rat retinas

作者：Juncai He, Yan Fu, Lingling Ge, Jiaman Dai, Yajie Fang, Yijian Li, Xianliang Gu, Zui Tao, Ting Zou, Minghui Li, Yong Liu, Haiwei Xu, Zheng Qin Yin · 发表于：Theranostics · 年份：2022 · DOI：10.7150/thno.67954 · 被引用次数：27 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Retinal Diseases and Treatments、Retinal Development and Disorders

Retinitis pigmentosa initially presents as night blindness owing to defects in rods, and the secondary degeneration of cones ultimately leads to blindness. Previous studies have identified active roles of microglia in the pathogenesis of photoreceptor degeneration in RP. However, the contribution of microglia to photoreceptor degeneration remains controversial, partly due to limited knowledge of microglial phenotypes during RP. Rationale: In this study, we investigated the pathways of microglial activation and its contribution to photoreceptor degeneration in RP. Methods: A classic RP model, Royal College of Surgeons rat, was used to explore the process of microglial activation during the development of RP. An inhibitor of colony-stimulating factor 1 receptor (PLX3397) was fed to RCS rats for sustained ablation of microglia. Immunohistochemistry, flow cytometry, RT-qPCR, electroretinography and RNA-Seq were used to investigate the mechanisms by which activated microglia influenced photoreceptor degeneration. Results: Microglia were gradually activated to disease-associated microglia in the photoreceptor layers of RCS rats. Sustained treatment with PLX3397 ablated most of the disease-associated microglia and aggravated photoreceptor degeneration, including the secondary degeneration of cones, by downregulating the expression of genes associated with photoreceptor function and components and exacerbating the impairment of photoreceptor cell function. Disease-associated microgli...