Downregulation of nutrition sensor GCN2 in macrophages contributes to poor wound healing in diabetes
Yangxiao Hou,
Dong Wei,
Zhaoqi Zhang,
Tong Lei,
Sihong Li,
Jiaming Bao,
Han Guo,
Liang Tan,
Xubiao Xie,
Yuan Zhuang,
Zhongbing Lu,
Yong Zhao
Affiliations
Yangxiao Hou
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
Dong Wei
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China; CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Shenzhen, China
Zhaoqi Zhang
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China; CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Shenzhen, China
Tong Lei
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China; Beijing Institute for Stem Cell and Regeneration, Beijing, China
Sihong Li
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
Jiaming Bao
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
Han Guo
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
Liang Tan
Kidney Transplantation Department, Second Xiangya Hospital of Central South University, Changsha, China
Xubiao Xie
Kidney Transplantation Department, Second Xiangya Hospital of Central South University, Changsha, China
Yuan Zhuang
Department of Blood Transfusion, First Medical Center of Chinese PLA General Hospital, Beijing, China
Zhongbing Lu
University of Chinese Academy of Sciences, Beijing, China; Corresponding author
Yong Zhao
State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China; University of Chinese Academy of Sciences, Beijing, China; CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China; Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Shenzhen, China; Beijing Institute for Stem Cell and Regeneration, Beijing, China; Corresponding author
Summary: Poor skin wound healing, which is common in patients with diabetes, is related to imbalanced macrophage polarization. Here, we find that nutrition sensor GCN2 (general control nonderepressible 2) and its downstream are significantly upregulated in human skin wound tissue and mouse skin wound macrophages, but skin wound-related GCN2 expression and activity are significantly downregulated by diabetes and hyperglycemia. Using wound healing models of GCN2-deleted mice, bone marrow chimeric mice, and monocyte-transferred mice, we show that GCN2 deletion in macrophages significantly delays skin wound healing compared with wild-type mice by altering M1 and M2a/M2c polarization. Mechanistically, GCN2 inhibits M1 macrophages via OXPHOS-ROS-NF-κB pathway and promotes tissue-repairing M2a/M2c macrophages through eukaryotic translation initiation factor 2 (eIF2α)-hypoxia-inducible factor 1α (HIF1α)-glycolysis pathway. Importantly, local supplementation of GCN2 activator halofuginone efficiently restores wound healing in diabetic mice with re-balancing M1 and M2a/2c polarization. Thus, the decreased macrophage GCN2 expression and activity contribute to poor wound healing in diabetes and targeting GCN2 improves wound healing in diabetes.
