Elevated microglial oxidative phosphorylation and phagocytosis stimulate post-stroke brain remodeling and cognitive function recovery in mice

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 (pH(i)) 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-Cre(ER+/-);Nhe1(flox/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. Song et al. use transgenic mice lacking the Na/H exchanger specifically in microglia to show that microglial oxidative phosphorylation plays a key role in post-stroke brain tissue repair and cognitive recovery. Their data is suggestive of a microglial metabolism signaling pathway that could constitute a potential therapeutic target in the context of stroke.

Automated summary

New research shows that disease-associated microglia in neurodegenerative brains have elevated phagocytosis, lysosomal functions, and lipid metabolism, which benefit brain repair. The study also reveals that genetic blockade of microglial NHE1 stimulates oxidative phosphorylation and boosts phagocytosis function, which is associated with tissue remodeling and post-stroke cognitive function recovery.