Microglial Function Is Distinct in Different Anatomical Locations during Retinal Homeostasis and Degeneration
Microglial Function Is Distinct in Different Anatomical Locations during Retinal Homeostasis and Degeneration
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DOI：
10.1016/j.immuni.2019.02.007
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发表时间：
2019-03-19
期刊：
影响因子：
32.4
通讯作者：
Saban, Daniel R.
中科院分区：
文献类型：
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作者：
O'Koren, Emily G.;Yu, Chen;Saban, Daniel R.
来自不同神经系统区域的小胶质细胞在分子和解剖学上是不同的，但它们是否也具有不同的功能尚不清楚。我们将谱系追踪、单细胞转录组学和小鼠视网膜电生理学结合起来，发现成年视网膜小胶质细胞具有共同的发育谱系，寿命长，但存在于两个不同的生态位中。这些小胶质细胞对白细胞介素-34的依赖性和对视觉信息处理的功能贡献有所不同。在某些视网膜变性模型中，来自两个池的小胶质细胞迁移到视网膜下空间，这是一个可诱导的疾病相关的生态位，单核细胞来源的细胞很难进入。这种小胶质细胞转变涉及小胶质细胞的转录重编程，其特征是稳态检查点基因的表达减少和损伤反应基因的上调。这种转变与保护视网膜色素上皮免受疾病引起的损伤有关。总之，我们的数据表明，小胶质细胞的功能因视网膜生态位而异，从而揭示了小胶质细胞异质性的重要性。
Microglia from different nervous system regions are molecularly and anatomically distinct, but whether they also have different functions is unknown. We combined lineage tracing, single-cell transcriptomics, and electrophysiology of the mouse retina and showed that adult retinal microglia shared a common developmental lineage and were long-lived but resided in two distinct niches. Microglia in these niches differed in their interleukin-34 dependency and functional contribution to visual-information processing. During certain retinal-degeneration models, microglia from both pools relocated to the subretinal space, an inducible disease-associated niche that was poorly accessible to monocyte-derived cells. This microglial transition involved transcriptional reprogramming of microglia, characterized by reduced expression of homeostatic checkpoint genes and upregulation of injury-responsive genes. This transition was associated with protection of the retinal pigmented epithelium from damage caused by disease. Together, our data demonstrate that microglial function varies by retinal niche, thereby shedding light on the significance of microglia heterogeneity.