Myeloid Slc2a1-Deficient Murine Model Revealed Macrophage Activation and
Metabolic Phenotype Are Fueled by GLUT1.
Authors Freemerman AJ, Zhao L, Pingili AK, Teng B, Cozzo AJ, Fuller AM, Johnson AR,
Milner JJ, Lim MF, Galanko JA, Beck MA, Bear JE, Rotty JD, Bezavada L, Smallwood
HS, Puchowicz MA, Liu J, Locasale JW, Lee DP, Bennett BJ, Abel ED, Rathmell JC,
Makowski L
Submitted By Submitted Externally on 10/14/2019
Status Published
Journal Journal of immunology (Baltimore, Md. : 1950)
Year 2019
Date Published 2/1/2019
Volume : Pages 202 : 1265 - 1286
PubMed Reference 30659108
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
Slc2a1M-/- 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.
Slc2a1M-/- BMDMs displayed a mixed inflammatory phenotype with reductions of the
classically activated pro- and anti-inflammatory markers, yet less oxidative
stress. Slc2a1M-/- 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 Slc2a1M-/- 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 Slc2a1M-/- 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.

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