PDF(Pubmed)
Abstract：
Microglia are the resident innate immune cells in the brain with a major role in orchestrating immune responses. They also provide a frontline of host defense in the central nervous system (CNS) through their active phagocytic capability. Being a professional phagocyte, microglia participate in phagocytic and autophagic clearance of cellular waste and debris as well as toxic protein aggregates, which relies on optimal lysosomal acidification and function. Defective microglial lysosomal acidification leads to impaired phagocytic and autophagic functions which result in the perpetuation of neuroinflammation and progression of neurodegeneration. Reacidification of impaired lysosomes in microglia has been shown to reverse neurodegenerative pathology in Alzheimer\'s disease. In this review, we summarize key factors and mechanisms contributing to lysosomal acidification impairment and the associated phagocytic and autophagic dysfunction in microglia, and how these defects contribute to neuroinflammation and neurodegeneration. We further discuss techniques to monitor lysosomal pH and therapeutic agents that can reacidify impaired lysosomes in microglia under disease conditions. Finally, we propose future directions to investigate the role of microglial lysosomal acidification in lysosome-mitochondria crosstalk and in neuron-glia interaction for more comprehensive understanding of its broader CNS physiological and pathological implications.
摘要：
小胶质细胞是大脑中固有的先天免疫细胞，在协调免疫反应中起着重要作用。它们还通过其主动吞噬能力在中枢神经系统(CNS)中提供宿主防御的前线。作为一个专业的吞噬细胞，小胶质细胞参与吞噬和自噬清除细胞废物和碎片以及有毒蛋白质聚集体，这依赖于最佳的溶酶体酸化和功能。缺陷的小胶质细胞溶酶体酸化导致吞噬和自噬功能受损，从而导致神经炎症的持续存在和神经变性的进展。小胶质细胞中受损溶酶体的再酸化已被证明可以逆转阿尔茨海默病的神经退行性病理。在这次审查中,我们总结了导致小胶质细胞溶酶体酸化损害和相关的吞噬和自噬功能障碍的关键因素和机制。以及这些缺陷如何导致神经炎症和神经变性。我们进一步讨论了监测溶酶体pH和治疗剂的技术，这些治疗剂可以在疾病条件下使小胶质细胞中受损的溶酶体重新适应。最后,我们提出了研究小胶质细胞溶酶体酸化在溶酶体-线粒体串扰和神经元-胶质细胞相互作用中的作用的未来方向,以便更全面地了解其更广泛的CNS生理和病理意义.
