Species-specific metabolic reprogramming in human and mouse microglia during inflammatory pathway induction

Metabolic reprogramming is considered a hallmark of murine macrophages and microglia response to inflammatory stimuli. Alterations in metabolic pathways include oxidative phosphorylation, glycolysis, the pentose phosphate pathway, and fatty acid oxidation. Mouse immune cells can switch their metabolism from mitochondrial oxidative phosphorylation (OXPHOS) to glycolysis in response to inflammatory conditions. The potential targeting of these metabolic pathways led to an exponential surge of interest in reprogramming metabolic pathways. However, most of these experimental findings have been acquired in murine immune cells. Limited information on metabolic reprogramming in human immune cells, including innate brain immune cells, is available. Studies of human microglia have been hindered by the limited availability of human brain microglia availability. In this study, we investigated transcriptomic and metabolic profiles in mouse and iPSC-derived human microglia challenged with TLR4 agonist LPS. We analyzed and compared the transcriptome profiles, phagocytosis, and metabolism of microglia from mouse and human by various methods, including RNA-seq, Incucyte imaging, xCELLigence real-time impedance measurements, extracellular acidification rate and oxygen consumption rate (OCR). We observed a metabolic shift and an overall increased glycolytic gene signature upon LPS treatment in both species. However, the dysregulation of oxidative metabolism was discrepant among species: mouse microglia exhibited a decrease in mitochondrial respiration after long-term LPS treatment, while human microglia did show a decrease after short-term LPS treatment. This study highlights the species-specific pathways involved in immunometabolism, linking the glycolytic metabolic switch without a necessary attenuation of respiration to classical inflammatory phenotypes in human microglia, and providing an informative report for future translational studies in mouse models and humans. Overall design: Comparative gene expression profiling analysis of RNA-seq data of mouse primary microglia, mouse acutely isolated microglia, and human iPSC-derived microglia-like cells.