GLUT3 Promotes Macrophage Signaling and Function via Ras-Mediated Endocytosis in Atopic Dermatitis and Wound Healing

Authors

Dong-Min Yu
Jiawei Zhao
Eunice E Lee
Dohun Kim
Ruchika Mahapatra
Elysha K Rose
Zhiwei Zhou
Calvin Hosler
Abdullah El Kurdi
Jun-Yong Choe
E Dale Abel
Gerta Hoxhaj
Kenneth D Westover
Raymond J Cho
Jeffrey B Cheng
Richard C Wang

Language

English

Publication Date

11-1-2023

Journal

Journal of Clinical Investigation

DOI

10.1172/JCI170706

PMID

37721853

PMCID

PMC10617774

PubMedCentral® Posted Date

11-1-2023

PubMedCentral® Full Text Version

Post-print

Abstract

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 patients with atopic dermatitis showed increased GLUT3 expression, and a calcipotriol-induced model of atopic dermatitis was rescued in LysM-Cre Glut3fl/fl mice. M2-like macrophages expressed GLUT3 in human wound tissues as assessed by transcriptomics and costaining, and GLUT3 expression was significantly decreased in nonhealing, 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, independently of its glucose transport activity. Unlike plasma membrane-localized GLUT1, GLUT3 was localized primarily to endosomes and was required for the efficient endocytosis of IL-4Rα subunits. GLUT3 interacted directly with GTP-bound RAS in vitro and in vivo through its intracytoplasmic loop domain, 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.

Keywords

Animals, Humans, Mice, Dermatitis, Atopic, Endocytosis, Glucose, Glucose Transporter Type 1, Glucose Transporter Type 3, Interleukin-4, Macrophage Activation, Macrophages, Wound Healing, Dermatology, Immunology, Glucose metabolism, Macrophages, Skin

Published Open-Access

yes

Recommended Citation

Yu, Dong-Min; Zhao, Jiawei; Lee, Eunice E; et al., "GLUT3 Promotes Macrophage Signaling and Function via Ras-Mediated Endocytosis in Atopic Dermatitis and Wound Healing" (2023). Staff and Researcher Publications. 27.
https://digitalcommons.library.tmc.edu/clinic_pub/27