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 investigated the transcriptomic and metabolic profiles of mouse and iPSC-derived human microglia challenged with the TLR4 agonist LPS. We found that both species displayed a metabolic shift and an overall increased glycolytic gene signature in response to LPS treatment. The metabolic reprogramming was characterized by the upregulation of hexokinases in mouse microglia and phosphofructokinases in human microglia. This study provides the first direct comparison of energy metabolism between mouse and human microglia, highlighting the species-specific pathways involved in immunometabolism and the importance of considering these differences in translational research.

An adapted protocol to derive microglia from stem cells and its application in the study of CSF1R-related disorders

“…High glucose concentrations can mask cellular phenotype resulting from genetic manipulations or variants, especially if it relates to cellular metabolism [31]. Furthermore, energy metabolism is intricately linked to immune function of microglia [32,33], with glucose concentration influencing microglial inflammatory response to LPS [34]. MEMα containing physiological concentration of glucose (5.6 mM) was therefore used as the base of the 2.9 microglia differentiation medium, instead of DMEM/F12 in the 2.0 medium which contains three times higher concentration of glucose (17.5 mM).…”

Metabolic flexibility ensures proper neuronal network function in moderate neuroinflammation

“…Microglia also interact with astrocytes in the juxtavascular space, where they can participate in the regulation of blood-brain barrier integrity and cerebral blood flow 19 . Importantly, microglia can be more glycolytic and present higher glucose uptake than neurons and glial cells in healthy 20 and diseased brain tissue 21 , a phenotype also observed in induced pluripotent stem cells (iPSC)-derived human microglia 22 . Indeed, microglia mediate a local increase in glucose consumption and lactate production in inflamed cortical tissue, further suggesting that these cells may alter energy substrate availability in the brain 13,23 .…”

“…1b), the gene encoding the enzyme producing itaconate, were strongly induced by LPS, and might represent an important source of carbon deviation from the Krebs cycle 13,34,35 . Since LPS already induces metabolic alterations after a few hours in microglial monocultures 13,22,36 , we next tested if changes in metabolism also occur early at the tissue level. Although inflammatory markers were identified in slice culture supernatants after 6 h, metabolic changes were first seen after 8 h of LPS treatment (Supplementary Fig.…”

Cardiac fibrogenesis: an immuno-metabolic perspective

“…Metabolic reprogramming allows the cells to adopt dynamic changes in cellular metabolic pathways and biological functions in response to various stimuli or environmental conditions, for example, cellular metabolism switches from oxidative metabolism (i.e., oxidative phosphorylation, OXPHOS) to the more oxygen-sparing carbohydrate metabolism (i.e., glycolysis) and utilization of glutamine and fatty acid increases to meet the energy and biosynthetic demands during acute and chronic cardiac stress (Sun et al, 2020a;Sabogal-Guáqueta et al, 2023;Ritterhoff and Tian, 2017;Rosano and Vitale, 2018;Yoganathan et al, 2023;Razeghi et al, 2001;Akki et al, 2008;Aubert et al, 2016;Bedi et al, 2016;Tran and Wang, 2019;Lin et al, 2023). With progressive low-grade inflammation in the background of cardiac insult, cytokines and nutrient metabolites activate inflammatory programs through shared pathways, and resident and recruited immune cells undergo metabolic shifts on their own as well during fibrotic events (Sun et al, 2020a;Sabogal-Guáqueta et al, 2023). The energy demand and metabolic intermediates for immune cell activation and differentiation are dependent more on glycolysis than on the tricarboxylic acid (TCA) cycle and OXPHOS (Srivastava et al, 2018;Cho et al, 2020;Farah et al, 2021;Wenzl et al, 2021).…”