Exosomes derived from microglia exposed to elevated pressure amplify the neuroinflammatory response in retinal cells
Exosomes derived from microglia exposed to elevated pressure amplify the neuroinflammatory response in retinal cells
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DOI：
10.1002/glia.23880
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发表时间：
2020-07-09
期刊：
影响因子：
6.2
通讯作者：
Santiago, Ana Raquel
中科院分区：
文献类型：
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作者：
Aires, Ines Dinis;Ribeiro-Rodrigues, Teresa;Santiago, Ana Raquel
青光眼是一种导致不可逆视力丧失的退行性疾病，其特征在于视网膜神经节细胞（RGC）丧失。其他人和我们已经证明，由反应性小胶质细胞介导的慢性神经炎症在胶质瘤病理学中起作用。外泌体是由大多数细胞（包括小胶质细胞）释放的细胞外囊泡，其介导细胞间通讯。小胶质细胞外泌体在脑胶质瘤变性中的作用仍不清楚。鉴于小胶质细胞外泌体在脑神经退行性疾病中的突出作用，我们研究了小胶质细胞源性外泌体对实验性青光眼炎症反应的贡献。将小胶质细胞暴露于升高的静水压力（EHP），以模拟升高的眼内压，这是青光眼的主要危险因素。将幼稚小胶质细胞（BV-2细胞或视网膜小胶质细胞）暴露于EHP条件下（BV-Exo-EHP）或在对照压力下培养（BV-Exo-Control）的源自BV-2细胞的外来体。我们发现BV-Exo-EHP增加促炎细胞因子的产生，促进视网膜小胶质细胞运动，吞噬效率和增殖。此外，原代视网膜神经细胞培养物与BV-Exo-EHP的孵育增加了细胞死亡和活性氧的产生。将源自视网膜小胶质细胞的外来体（MG-Exo-Control或MG-Exo-EHP）注射到C57 BL/6 J小鼠的玻璃体中。MG-Exo-EHP持续激活视网膜小胶质细胞，介导细胞死亡，并影响RGC数量。在本文中，我们表明，来自视网膜小胶质细胞的外泌体具有自分泌功能，并在压力升高的条件下传播炎症信号，从而导致视网膜变性。
Glaucoma is a degenerative disease that causes irreversible loss of vision and is characterized by retinal ganglion cell (RGC) loss. Others and we have demonstrated that chronic neuroinflammation mediated by reactive microglial cells plays a role in glaucomatous pathology. Exosomes are extracellular vesicles released by most cells, including microglia, that mediate intercellular communication. The role of microglial exosomes in glaucomatous degeneration remains unknown. Taking the prominent role of microglial exosomes in brain neurodegenerative diseases, we studied the contribution of microglial-derived exosomes to the inflammatory response in experimental glaucoma. Microglial cells were exposed to elevated hydrostatic pressure (EHP), to mimic elevated intraocular pressure, the main risk factor for glaucoma. Naive microglia (BV-2 cells or retinal microglia) were exposed to exosomes derived from BV-2 cells under EHP conditions (BV-Exo-EHP) or cultured in control pressure (BV-Exo-Control). We found that BV-Exo-EHP increased the production of pro-inflammatory cytokines, promoted retinal microglia motility, phagocytic efficiency, and proliferation. Furthermore, the incubation of primary retinal neural cell cultures with BV-Exo-EHP increased cell death and the production of reactive oxygen species. Exosomes derived from retinal microglia (MG-Exo-Control or MG-Exo-EHP) were injected in the vitreous of C57BL/6J mice. MG-Exo-EHP sustained activation of retinal microglia, mediated cell death, and impacted RGC number. Herein, we show that exosomes derived from retinal microglia have an autocrine function and propagate the inflammatory signal in conditions of elevated pressure, contributing to retinal degeneration in glaucomatous conditions.