| First Author | Freemerman AJ | Year | 2019 |
| Journal | J Immunol | Volume | 202 |
| Issue | 4 | Pages | 1265-1286 |
| PubMed ID | 30659108 | Mgi Jnum | J:272884 |
| Mgi Id | MGI:6280736 | Doi | 10.4049/jimmunol.1800002 |
| Citation | Freemerman AJ, et al. (2019) Myeloid Slc2a1-Deficient Murine Model Revealed Macrophage Activation and Metabolic Phenotype Are Fueled by GLUT1. J Immunol 202(4):1265-1286 |
| abstractText | Macrophages (MPhis) 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 MPhi activation. We created a murine model of myeloid-specific glucose transporter GLUT1 (Slc2a1) deletion. Bone marrow-derived MPhis (BMDM) from Slc2a1(M-/-) 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 MPhi lacking GLUT1, demonstrating an incomplete metabolic reprogramming. Slc2a1(M-/-) BMDMs displayed a mixed inflammatory phenotype with reductions of the classically activated pro- and anti-inflammatory markers, yet less oxidative stress. Slc2a1(M-/-) 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 MPhis of lean Slc2a1(M-/-) 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(-/-) mice lacking myeloid GLUT1 developed unstable atherosclerotic lesions. Defective phagocytic capacity in Slc2a1(M-/-) BMDMs may have contributed to unstable atheroma formation. Together, our findings suggest that although lack of GLUT1 blunted glycolysis and the pentose phosphate pathway, MPhi were metabolically flexible enough that inflammatory cytokine release was not dramatically regulated, yet phagocytic defects hindered MPhi function in chronic diseases. |
