Myeloid Slc2a1-Deficient Murine Model Revealed Macrophage Activation and Metabolic Phenotype Are Fueled by GLUT1

Abstract

Macrophages (MFs) are heterogeneous and metabolically flexible, with metabolism strongly affecting immune activation. A classic response to proinflammatory activation is increased flux through glycolysis with a downregulation of oxidative metabolism, whereas alternative activation is primarily oxidative, which begs the question of whether targeting glucose metabolism is a viable approach to control MF activation. We created a murine model of myeloid-specific glucose transporter GLUT1 (Slc2a1) deletion. Bone marrow-derived MFs (BMDM) from Slc2a1 M2/2 mice failed to uptake glucose and demonstrated reduced glycolysis and pentose phosphate pathway activity. Activated BMDMs displayed elevated metabolism of oleate and glutamine, yet maximal respiratory capacity was blunted in MF lacking GLUT1, demonstrating an incomplete metabolic reprogramming. Slc2a1 M2/2 BMDMs displayed a mixed inflammatory phenotype with reductions of the classically activated pro-and anti-inflammatory markers, yet less oxidative stress. Slc2a1 M2/2 BMDMs had reduced proinflammatory metabolites, whereas metabolites indicative of alternative activation-such as ornithine and polyamines-were greatly elevated in the absence of GLUT1. Adipose tissue MFs of lean Slc2a1 M2/2 mice had increased alternative M2-like activation marker mannose receptor CD206, yet lack of GLUT1 was not a critical mediator in the development of obesity-associated metabolic dysregulation. However, Ldlr 2/2 mice lacking myeloid GLUT1 developed unstable atherosclerotic lesions. Defective phagocytic capacity in Slc2a1 M2/2 BMDMs may have contributed to unstable atheroma formation. Together, our findings suggest that although lack of GLUT1 blunted glycolysis and the pentose phosphate pathway, MF were metabolically flexible enough that inflammatory cytokine release was not dramatically regulated, yet phagocytic defects hindered MF function in chronic diseases.

Immunometabolism: From basic mechanisms to translation

“…9,53 Indeed, transgenic expression of Glut1 increased classically activated macrophage inflammatory function, while genetic deletion of Glut1 specifically repressed those functions. 54,55 Lastly, Bakker and Pearce touch upon the role of mitochondrial metabolism downstream of a little studied pathway called hypusination through the polyamine spermidine derived from arginine, an amino acid well studied in macrophage metabolism. 56 Inhibition of hypusination of eukaryotic initiation factor 5 (eIF5A) led to the reduction of alternatively activated macrophage markers, TCA cycle flux, fewer electron transport chain (ETC) components, and an overall reduced OXPHOS metabolism.…”

Adipose tissue macrophages: Unique polarization and bioenergetics in obesity

“…Makowski's group found a similar phenotype to Stienstra's group, with glycolytic macrophages expressing high levels of the glucose transporter, Glut 1; however, paradoxically, Glut1 myeloid knockout mice were not protected against diet-induced obesity. 55 Moreover, while obese ATMs have increased expression of the fatty acid transporter Fatp1, Fatp1 deficient mice have worsened weight gain and glucose tolerance following HFD-feeding. 56…”

Microbiome, bile acids, and obesity: How microbially modified metabolites shape anti‐tumor immunity

“…Yet in vivo and recent in vitro studies underscore that classical and alternative phenotypes are not dichotomous but rather present overlapping phenotypes and flexible metabolism. 162,[281][282][283][284] Work completed by our group and others demonstrated that obesity is associated with low-grade adipose inflammation and crown-like structures (CLS) in fat depots throughout the body including subcutaneous and visceral adipose 162,165,283 as well as the lesser studied fat depot of the normal human breast in humans, non-human primates, and mammary gland in mice. 79,[152][153][154][155][156][157][158][159][160][161][162][163][164] In visceral fat, macrophages can comprise up to 50% of the cellularity of an adipose depot.…”