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

• DOI: 10.1016/j.celrep.2023.113658
• Publication Date: 2024-01-03T16:31:53Z
• Authors: Yangxiao Hou; Dong Wei; Zhaoqi Zhang; Tong Lei; Sihong Li; Jiaming Bao; Han Guo; Liang Tan; Xubiao Xie; Yuan Zhuang; Zhongbing Lu; Yong Zhao
• Keywords: 0301 basic medicine; 03 medical and health sciences; QH301-705.5; CP: Immunology; Biology (General)

Poor skin wound healing, which is common in patients with diabetes, related to imbalanced macrophage polarization. Here, we find that nutrition sensor GCN2 (general control nonderepressible 2) and its downstream are significantly upregulated human tissue mouse macrophages, but wound-related expression activity downregulated by diabetes hyperglycemia. Using healing models of GCN2-deleted mice, bone marrow chimeric monocyte-transferred show deletion macrophages delays compared wild-type mice altering M1 M2a/M2c Mechanistically, inhibits via OXPHOS-ROS-NF-κB pathway promotes tissue-repairing through eukaryotic translation initiation factor 2 (eIF2α)-hypoxia-inducible 1α (HIF1α)-glycolysis pathway. Importantly, local supplementation activator halofuginone efficiently restores diabetic re-balancing M2a/2c Thus, the decreased contribute poor targeting improves diabetes.