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Author Spotlight: Establishing a Reliable Distal MCA Occlusion Model in Mice for Stroke Research
Published on: December 15, 2023
Elevated microglial oxidative phosphorylation and phagocytosis stimulate post-stroke brain remodeling and cognitive
Shanshan Song1,2, Lauren Yu3,4, Md Nabiul Hasan3,4
1Dept. of Neurology, Univ. of Pittsburgh, Pittsburgh, PA, USA. songs2@upmc.edu.
Abstract:
New research shows that disease-associated microglia in neurodegenerative brains present features of elevated phagocytosis, lysosomal functions, and lipid metabolism, which benefit brain repair. The underlying mechanisms remain poorly understood. Intracellular pH (pHi) is important for regulating aerobic glycolysis in microglia, where Na/H exchanger (NHE1) is a key pH regulator by extruding H+ in exchange of Na+ influx. We report here that post-stroke Cx3cr1-CreER+/-;Nhe1flox/flox (Nhe1 cKO) brains displayed stimulation of microglial transcriptomes of rate-limiting enzyme genes for glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. The other upregulated genes included genes for phagocytosis and LXR/RXR pathway activation as well as the disease-associated microglia hallmark genes (Apoe, Trem2, Spp1). The cKO microglia exhibited increased oxidative phosphorylation capacity, and higher phagocytic activity, which likely played a role in enhanced synaptic stripping and remodeling, oligodendrogenesis, and remyelination. This study reveals that genetic blockade of microglial NHE1 stimulated oxidative phosphorylation immunometabolism, and boosted phagocytosis function which is associated with tissue remodeling and post-stroke cognitive function recovery.
Insights
Blocking microglial Na/H exchanger 1 (NHE1) enhances brain repair after stroke. This genetic intervention boosts microglial phagocytosis and oxidative phosphorylation, aiding cognitive function recovery.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Disease-associated microglia (DAM) exhibit enhanced phagocytosis, lysosomal function, and lipid metabolism, crucial for brain repair in neurodegenerative diseases.
- Intracellular pH (pHi) regulation is vital for microglial function, with the Na/H exchanger 1 (NHE1) playing a key role in maintaining pH homeostasis.
Purpose of the Study:
- To investigate the role of microglial NHE1 in regulating microglial immunometabolism and function, particularly in the context of post-stroke brain repair.
- To determine the impact of genetically blocking microglial NHE1 on microglial transcriptomes, phagocytic activity, and overall brain recovery after stroke.
Main Methods:
- Utilized a stroke model in Cx3cr1-CreER+/-;Nhe1flox/flox (Nhe1 cKO) mice to genetically ablate NHE1 specifically in microglia.
- Analyzed microglial transcriptomes to assess changes in metabolic pathways, phagocytosis-related genes, and DAM hallmark genes.
- Assessed microglial oxidative phosphorylation capacity and phagocytic activity in Nhe1 cKO brains.
Main Results:
- Genetic blockade of microglial NHE1 led to upregulated expression of genes involved in glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation.
- Nhe1 cKO microglia showed enhanced phagocytic activity and increased oxidative phosphorylation capacity.
- Upregulation of hallmark disease-associated microglia genes (Apoe, Trem2, Spp1) and LXR/RXR pathway activation was observed in Nhe1 cKO brains.
Conclusions:
- Genetic inhibition of microglial NHE1 stimulates oxidative phosphorylation and enhances microglial phagocytosis, contributing to beneficial tissue remodeling and synaptic repair post-stroke.
- Targeting microglial NHE1 represents a potential therapeutic strategy to promote cognitive function recovery after stroke by modulating microglial immunometabolism and phagocytic functions.
