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ResearchIn-Press PreviewDermatologyImmunology
Open Access | 10.1172/JCI170706
1Department of Dermatology, UT Southwestern Medical Center, Dallas, United States of America
2Division of Hematology/Oncology, Harvard Medical School, Boston, United States of America
3Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, United States of America
4Departments of Biochemistry and Radiation Oncology, UT Southwestern Medical Center, Dallas, United States of America
5Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
6Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, United States of America
7Department of Medicine, UCLA, Los Angeles, United States of America
8Department of Dermatology, UCSF, San Francisco, United States of America
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1Department of Dermatology, UT Southwestern Medical Center, Dallas, United States of America
2Division of Hematology/Oncology, Harvard Medical School, Boston, United States of America
3Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, United States of America
4Departments of Biochemistry and Radiation Oncology, UT Southwestern Medical Center, Dallas, United States of America
5Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
6Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, United States of America
7Department of Medicine, UCLA, Los Angeles, United States of America
8Department of Dermatology, UCSF, San Francisco, United States of America
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1Department of Dermatology, UT Southwestern Medical Center, Dallas, United States of America
2Division of Hematology/Oncology, Harvard Medical School, Boston, United States of America
3Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, United States of America
4Departments of Biochemistry and Radiation Oncology, UT Southwestern Medical Center, Dallas, United States of America
5Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
6Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, United States of America
7Department of Medicine, UCLA, Los Angeles, United States of America
8Department of Dermatology, UCSF, San Francisco, United States of America
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1Department of Dermatology, UT Southwestern Medical Center, Dallas, United States of America
2Division of Hematology/Oncology, Harvard Medical School, Boston, United States of America
3Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, United States of America
4Departments of Biochemistry and Radiation Oncology, UT Southwestern Medical Center, Dallas, United States of America
5Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
6Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, United States of America
7Department of Medicine, UCLA, Los Angeles, United States of America
8Department of Dermatology, UCSF, San Francisco, United States of America
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1Department of Dermatology, UT Southwestern Medical Center, Dallas, United States of America
2Division of Hematology/Oncology, Harvard Medical School, Boston, United States of America
3Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, United States of America
4Departments of Biochemistry and Radiation Oncology, UT Southwestern Medical Center, Dallas, United States of America
5Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
6Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, United States of America
7Department of Medicine, UCLA, Los Angeles, United States of America
8Department of Dermatology, UCSF, San Francisco, United States of America
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1Department of Dermatology, UT Southwestern Medical Center, Dallas, United States of America
2Division of Hematology/Oncology, Harvard Medical School, Boston, United States of America
3Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, United States of America
4Departments of Biochemistry and Radiation Oncology, UT Southwestern Medical Center, Dallas, United States of America
5Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
6Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, United States of America
7Department of Medicine, UCLA, Los Angeles, United States of America
8Department of Dermatology, UCSF, San Francisco, United States of America
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1Department of Dermatology, UT Southwestern Medical Center, Dallas, United States of America
2Division of Hematology/Oncology, Harvard Medical School, Boston, United States of America
3Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, United States of America
4Departments of Biochemistry and Radiation Oncology, UT Southwestern Medical Center, Dallas, United States of America
5Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
6Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, United States of America
7Department of Medicine, UCLA, Los Angeles, United States of America
8Department of Dermatology, UCSF, San Francisco, United States of America
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1Department of Dermatology, UT Southwestern Medical Center, Dallas, United States of America
2Division of Hematology/Oncology, Harvard Medical School, Boston, United States of America
3Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, United States of America
4Departments of Biochemistry and Radiation Oncology, UT Southwestern Medical Center, Dallas, United States of America
5Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
6Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, United States of America
7Department of Medicine, UCLA, Los Angeles, United States of America
8Department of Dermatology, UCSF, San Francisco, United States of America
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1Department of Dermatology, UT Southwestern Medical Center, Dallas, United States of America
2Division of Hematology/Oncology, Harvard Medical School, Boston, United States of America
3Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, United States of America
4Departments of Biochemistry and Radiation Oncology, UT Southwestern Medical Center, Dallas, United States of America
5Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
6Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, United States of America
7Department of Medicine, UCLA, Los Angeles, United States of America
8Department of Dermatology, UCSF, San Francisco, United States of America
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1Department of Dermatology, UT Southwestern Medical Center, Dallas, United States of America
2Division of Hematology/Oncology, Harvard Medical School, Boston, United States of America
3Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, United States of America
4Departments of Biochemistry and Radiation Oncology, UT Southwestern Medical Center, Dallas, United States of America
5Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
6Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, United States of America
7Department of Medicine, UCLA, Los Angeles, United States of America
8Department of Dermatology, UCSF, San Francisco, United States of America
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1Department of Dermatology, UT Southwestern Medical Center, Dallas, United States of America
2Division of Hematology/Oncology, Harvard Medical School, Boston, United States of America
3Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, United States of America
4Departments of Biochemistry and Radiation Oncology, UT Southwestern Medical Center, Dallas, United States of America
5Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
6Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, United States of America
7Department of Medicine, UCLA, Los Angeles, United States of America
8Department of Dermatology, UCSF, San Francisco, United States of America
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Abel, E.
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1Department of Dermatology, UT Southwestern Medical Center, Dallas, United States of America
2Division of Hematology/Oncology, Harvard Medical School, Boston, United States of America
3Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, United States of America
4Departments of Biochemistry and Radiation Oncology, UT Southwestern Medical Center, Dallas, United States of America
5Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
6Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, United States of America
7Department of Medicine, UCLA, Los Angeles, United States of America
8Department of Dermatology, UCSF, San Francisco, United States of America
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Hoxhaj, G.
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1Department of Dermatology, UT Southwestern Medical Center, Dallas, United States of America
2Division of Hematology/Oncology, Harvard Medical School, Boston, United States of America
3Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, United States of America
4Departments of Biochemistry and Radiation Oncology, UT Southwestern Medical Center, Dallas, United States of America
5Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
6Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, United States of America
7Department of Medicine, UCLA, Los Angeles, United States of America
8Department of Dermatology, UCSF, San Francisco, United States of America
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Westover, K.
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1Department of Dermatology, UT Southwestern Medical Center, Dallas, United States of America
2Division of Hematology/Oncology, Harvard Medical School, Boston, United States of America
3Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, United States of America
4Departments of Biochemistry and Radiation Oncology, UT Southwestern Medical Center, Dallas, United States of America
5Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
6Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, United States of America
7Department of Medicine, UCLA, Los Angeles, United States of America
8Department of Dermatology, UCSF, San Francisco, United States of America
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Cho, R.
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1Department of Dermatology, UT Southwestern Medical Center, Dallas, United States of America
2Division of Hematology/Oncology, Harvard Medical School, Boston, United States of America
3Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, United States of America
4Departments of Biochemistry and Radiation Oncology, UT Southwestern Medical Center, Dallas, United States of America
5Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
6Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, United States of America
7Department of Medicine, UCLA, Los Angeles, United States of America
8Department of Dermatology, UCSF, San Francisco, United States of America
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1Department of Dermatology, UT Southwestern Medical Center, Dallas, United States of America
2Division of Hematology/Oncology, Harvard Medical School, Boston, United States of America
3Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, United States of America
4Departments of Biochemistry and Radiation Oncology, UT Southwestern Medical Center, Dallas, United States of America
5Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
6Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, United States of America
7Department of Medicine, UCLA, Los Angeles, United States of America
8Department of Dermatology, UCSF, San Francisco, United States of America
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Published September 18, 2023 - More info
The facilitative GLUT1 and GLUT3 hexose transporters are expressed abundantly in macrophages, but whether they have distinct functions remains unclear. We confirmed that GLUT1 expression increased after M1 polarization stimuli and found that GLUT3 expression increased after M2 stimulation in macrophages. Conditional deletion of Glut3 (LysM-Cre Glut3fl/fl) impaired M2 polarization of bone marrow derived macrophages. Alternatively activated macrophages from the skin of atopic dermatitis patients showed increased GLUT3 expression, and a calcipotriol-induced model of atopic dermatitis was rescued LysM-Cre Glut3fl/fl mice. M2-like macrophages expressed GLUT3 in human wound tissues as assessed by transcriptomics and co-staining, and GLUT3 expression was significantly decreased in non-healing, compared with healing, diabetic foot ulcers. In an excisional wound healing model, LysM-Cre Glut3fl/fl mice showed significantly impaired M2 macrophage polarization and delayed wound healing. GLUT3 promoted IL-4/STAT6 signaling, independent from its glucose transport activity. Unlike plasma membrane-localized GLUT1, GLUT3 was localized primarily to endosomes and was required for the efficient endocytosis of IL4Ra subunits. GLUT3 interacted directly with GTP-bound RAS in vitro and in vivo through its intracytoplasmic loop domain (ICH), and this interaction was required for efficient STAT6 activation and M2 polarization. PAK activation and macropinocytosis were also impaired without GLUT3, suggesting broader roles for GLUT3 in the regulation of endocytosis. Thus, GLUT3 is required for efficient alternative macrophage polarization and function, through a glucose transport-independent, RAS-mediated role in the regulation of endocytosis and IL-4/STAT6 activation.