Downregulation of nutrition sensor GCN2 in macrophages contributes to poor wound healing in diabetes

• Published in: Cell reports (Cambridge) 2024-01, Vol.43 (1), p.113658-113658, Article 113658
• Main Authors: Hou, Yangxiao, Wei, Dong, Zhang, Zhaoqi, Lei, Tong, Li, Sihong, Bao, Jiaming, Guo, Han, Tan, Liang, Xie, Xubiao, Zhuang, Yuan, Lu, Zhongbing, Zhao, Yong
• Format: Article
• Language: English
• Subjects: CP: Immunology; diabetes; GCN2; macrophage polarization; macrophages; nutrition sensor; wound healing
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113658

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. [Display omitted] •GCN2 expression and activity are upregulated in macrophages during skin wound healing•GCN2 deficiency delays skin wound healing via imbalanced M1 and M2a/2c polarization•GCN2 controls M2a/2c polarization by regulating the eIF2α-HIF1α-glycolysis pathway•Local GCN2 agonist treatment rescues the delayed wound healing in diabetes Hou et al. report that GCN2 regulates M1 polarization via the OXPHOS-ROS-NF-κB pathway and M2a/M2c polarization via the eIF2α-HiF1α-glycolysis pathway, thereby regulating diabetic wound healing. The GCN2 activator HF accelerates skin wound healing in diabetic mice. This study provides a target for preventing delayed skin healing in patients with diabetes.