Lysosomal acidification dysfunction in microglia: an emerging pathogenic mechanism of neuroinflammation and neurodegeneration

Journal of Neuroinflammation

Review

Joseph D. Quick¹  Cristian Silva²  Jia Hui Wong³  Jialiu Zeng³  Anna M. Barron³  Chih Hung Lo³  Kah Leong Lim⁴  Richard Reynolds⁴ 

[1] Department of Integrative Biology and Physiology, Medical School, University of Minnesota, Minneapolis, MN, USA;Faculty of Graduate Studies, University of Kelaniya, Kelaniya, Sri Lanka;Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore;Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore;Department of Brain Sciences, Faculty of Medicine, Imperial College London, London, UK;

关键词: Lysosomal acidification;    Autophagy;    Phagocytosis;    Cytokines;    Toxic protein aggregates;    Neuroinflammation;    Neurodegenerative diseases;    Acidic nanoparticles;   

DOI  :  10.1186/s12974-023-02866-y

 received in 2023-06-12, accepted in 2023-07-30,  发布年份 2023

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY   
© BioMed Central Ltd., part of Springer Nature 2023

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