Lysosomal acidification dysfunction in microglia: an emerging pathogenic mechanism of neuroinflammation and neurodegeneration
File(s)
Author(s)
Type
Journal Article
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.
Date Issued
2023-08-05
Date Acceptance
2023-07-30
Citation
Journal of Neuroinflammation, 2023, 20 (1)
ISSN
1742-2094
Publisher
BMC
Journal / Book Title
Journal of Neuroinflammation
Volume
20
Issue
1
Copyright Statement
© The Author(s) 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
License URL
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/37543564
PII: 10.1186/s12974-023-02866-y
Subjects
Alzheimer Disease
Humans
Hydrogen-Ion Concentration
Lysosomes
Microglia
Neuroinflammatory Diseases
Acidic nanoparticles
Autophagy
Cytokines
Lysosomal acidification
Neurodegenerative diseases
Neuroinflammation
Phagocytosis
Toxic protein aggregates
Publication Status
Published
Coverage Spatial
England
Article Number
ARTN 185