Myeloid SLC2a1-deficient murine model revealed macrophage activation and metabolic phenotype are fueled by GLUT1

Alex J. Freemerman, Liyang Zhao, Ajeeth K. Pingili, Bin Teng, Alyssa J. Cozzo, Ashley M. Fuller, Amy R. Johnson, J. Justin Milner, Maili F. Lim, Joseph A. Galanko, Melinda A. Beck, James E. Bear, Jeremy D. Rotty, Lavanya Bezavada, Heather Smallwood, Michelle Puchowicz, Juan Liu, Jason W. Locasale, Douglas P. Lee, Brian J. Bennett & 3 others E. Dale Abel, Jeff C. Rathmell, Liza Makowski

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 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 MF 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 MFs 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, MF were metabolically flexible enough that inflammatory cytokine release was not dramatically regulated, yet phagocytic defects hindered MF function in chronic diseases.

Original languageEnglish (US)
Pages (from-to)1265-1286
Number of pages22
JournalJournal of Immunology
Volume202
Issue number4
DOIs
StatePublished - Jan 1 2019

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Macrophage Activation
Glycolysis
Phenotype
Pentose Phosphate Pathway
Glucose
Ornithine
Facilitative Glucose Transport Proteins
Polyamines
Atherosclerotic Plaques
Oleic Acid
Glutamine
Adipose Tissue
Oxidative Stress
Chronic Disease
Anti-Inflammatory Agents
Down-Regulation
Obesity
Bone Marrow
Macrophages
Cytokines

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Freemerman, A. J., Zhao, L., Pingili, A. K., Teng, B., Cozzo, A. J., Fuller, A. M., ... Makowski, L. (2019). Myeloid SLC2a1-deficient murine model revealed macrophage activation and metabolic phenotype are fueled by GLUT1. Journal of Immunology, 202(4), 1265-1286. https://doi.org/10.4049/jimmunol.1800002

Myeloid SLC2a1-deficient murine model revealed macrophage activation and metabolic phenotype are fueled by GLUT1. / Freemerman, Alex J.; Zhao, Liyang; Pingili, Ajeeth K.; Teng, Bin; Cozzo, Alyssa J.; Fuller, Ashley M.; Johnson, Amy R.; Justin Milner, J.; Lim, Maili F.; Galanko, Joseph A.; Beck, Melinda A.; Bear, James E.; Rotty, Jeremy D.; Bezavada, Lavanya; Smallwood, Heather; Puchowicz, Michelle; Liu, Juan; Locasale, Jason W.; Lee, Douglas P.; Bennett, Brian J.; Dale Abel, E.; Rathmell, Jeff C.; Makowski, Liza.

In: Journal of Immunology, Vol. 202, No. 4, 01.01.2019, p. 1265-1286.

Research output: Contribution to journalArticle

Freemerman, AJ, Zhao, L, Pingili, AK, Teng, B, Cozzo, AJ, Fuller, AM, Johnson, AR, Justin Milner, J, Lim, MF, Galanko, JA, Beck, MA, Bear, JE, Rotty, JD, Bezavada, L, Smallwood, H, Puchowicz, M, Liu, J, Locasale, JW, Lee, DP, Bennett, BJ, Dale Abel, E, Rathmell, JC & Makowski, L 2019, 'Myeloid SLC2a1-deficient murine model revealed macrophage activation and metabolic phenotype are fueled by GLUT1', Journal of Immunology, vol. 202, no. 4, pp. 1265-1286. https://doi.org/10.4049/jimmunol.1800002
Freemerman, Alex J. ; Zhao, Liyang ; Pingili, Ajeeth K. ; Teng, Bin ; Cozzo, Alyssa J. ; Fuller, Ashley M. ; Johnson, Amy R. ; Justin Milner, J. ; Lim, Maili F. ; Galanko, Joseph A. ; Beck, Melinda A. ; Bear, James E. ; Rotty, Jeremy D. ; Bezavada, Lavanya ; Smallwood, Heather ; Puchowicz, Michelle ; Liu, Juan ; Locasale, Jason W. ; Lee, Douglas P. ; Bennett, Brian J. ; Dale Abel, E. ; Rathmell, Jeff C. ; Makowski, Liza. / Myeloid SLC2a1-deficient murine model revealed macrophage activation and metabolic phenotype are fueled by GLUT1. In: Journal of Immunology. 2019 ; Vol. 202, No. 4. pp. 1265-1286.
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AU - Freemerman, Alex J.

AU - Zhao, Liyang

AU - Pingili, Ajeeth K.

AU - Teng, Bin

AU - Cozzo, Alyssa J.

AU - Fuller, Ashley M.

AU - Johnson, Amy R.

AU - Justin Milner, J.

AU - Lim, Maili F.

AU - Galanko, Joseph A.

AU - Beck, Melinda A.

AU - Bear, James E.

AU - Rotty, Jeremy D.

AU - Bezavada, Lavanya

AU - Smallwood, Heather

AU - Puchowicz, Michelle

AU - Liu, Juan

AU - Locasale, Jason W.

AU - Lee, Douglas P.

AU - Bennett, Brian J.

AU - Dale Abel, E.

AU - Rathmell, Jeff C.

AU - Makowski, Liza

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N2 - 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 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 MF 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 MFs 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, 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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