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

Abstract

Metabolic reprogramming is a hallmark of the immune cells in response to inflammatory stimuli. This metabolic process involves a switch from oxidative phosphorylation (OXPHOS) to glycolysis or alterations in other metabolic pathways. However, most of the experimental findings have been acquired in murine immune cells, and little is known about the metabolic reprogramming of human microglia. In this study, we investigate the transcriptomic, proteomic, and metabolic profiles of mouse and iPSC-derived human microglia challenged with the TLR4 agonist LPS. We demonstrate that both species display a metabolic shift and an overall increased glycolytic gene signature in response to LPS treatment. The metabolic reprogramming is characterized by the upregulation of hexokinases in mouse microglia and phosphofructokinases in human microglia. This study provides a direct comparison of metabolism between mouse and human microglia, highlighting the species-specific pathways involved in immunometabolism and the importance of considering these differences in translational research.

Reduced synaptic depression in human neurons carrying homozygous disease-causing STXBP1 variant L446F

“…Finally, differences in cellular phenotypes between mouse and human neurons may result from intrinsic species differences. Such a difference has recently been shown in a study comparing mouse and human microglia [ 48 ]. Most studies on the functions of the release machinery and Munc18-1 have been conducted using rodent neurons.…”

Human Glial Cells as Innovative Targets for the Therapy of Central Nervous System Pathologies

“…For instance, human iPSC-derived microglia exposed to LPS displayed a metabolic shift, as already reported for the immortalized mouse microglial cell line BV-2 [76], and an overall increased glycolytic gene signature. At variance from mouse microglia, which in response to LPS treatment showed a metabolic reprogramming characterized by the upregulation of hexokinases, human microglia displayed upregulated phosphofructokinases, highlighting the species-specificity of the pathways involved in immunometabolism and the importance of considering these differences in translational research [77]. Acute exposure of human iPSC-derived microglia to IL-6, which at prenatal stages is associated with increased risk for psychiatric disorders, resulted in STAT3 phosphorylation and increased IL6, JMJD3 and IL10 gene expression, indicating the activation of IL-6Ra signaling.…”

A pharmacological toolkit for human microglia identifies Topoisomerase I inhibitors as immunomodulators for Alzheimer’s disease

“…While the currently available datasets propose different human microglial population structures, highlighting the limitations of current profiling technologies, certain patterns are emerging from these transcriptomic data, underscoring the need for a shared framework for nomenclature of human microglia. In particular, given the possible range of cellular metabolic states and mitochondrial phenotypes (i.e., mitotypes) that influence cellular behaviors 13 , a frame of reference for profiling bioenergetic profiles among microglia is needed 14 . The greater challenge however has been linking transcriptionally defined clusters of human microglia to key microglial functions.…”

“…It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted February 6, 2024. ; https://doi.org/10.1101/2024.02.06.579103 doi: bioRxiv preprint emerging from these transcriptomic data, underscoring the need for a shared framework for nomenclature of human microglia. In particular, given the possible range of cellular metabolic states and mitochondrial phenotypes (i.e., mitotypes) that influence cellular behaviors 13 , a frame of reference for profiling bioenergetic profiles among microglia is needed 14 . The greater challenge however has been linking transcriptionally defined clusters of human microglia to key microglial functions.…”