Aires Inês Dinis, Ribeiro-Rodrigues Teresa, Boia Raquel, Catarino Steve, Girão Henrique, Ambrósio António Francisco, Santiago Ana Raquel
Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, University of Coimbra, Coimbra, Portugal.
Center for Innovative Biomedicine and Biotechnology (CIBB), University of Coimbra, Coimbra, Portugal.
Glia. 2020 Dec;68(12):2705-2724. doi: 10.1002/glia.23880. Epub 2020 Jul 9.
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. Naïve 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.
青光眼是一种导致不可逆视力丧失的退行性疾病，其特征是视网膜神经节细胞（RGC）丢失。我们和其他人已经证明，由反应性小胶质细胞介导的慢性神经炎症在青光眼病理过程中起作用。外泌体是大多数细胞（包括小胶质细胞）释放的细胞外囊泡，介导细胞间通讯。小胶质细胞外泌体在青光眼性退变中的作用尚不清楚。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来源的外泌体在实验性青光眼中对炎症反应的贡献。小胶质细胞暴露于升高的静水压力（EHP）下，以模拟青光眼的主要危险因素——眼内压升高。未处理的小胶质细胞（BV-2细胞或视网膜小胶质细胞）在EHP条件下暴露于来自BV-2细胞的外泌体（BV-Exo-EHP），或在对照压力下培养（BV-Exo-Control）。我们发现BV-Exo-EHP增加了促炎细胞因子的产生，促进了视网膜小胶质细胞的运动性、吞噬效率和增殖。此外，用BV-Exo-EHP孵育原代视网膜神经细胞培养物会增加细胞死亡和活性氧的产生。将来自视网膜小胶质细胞的外泌体（MG-Exo-Control或MG-Exo-EHP）注射到C57BL/6J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。在此，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，并在压力升高的情况下传播炎症信号，导致青光眼状态下的视网膜退变。
