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Diabetic macrophage small extracellular vesicles-associated miR-503/IGF1R axis regulates endothelial cell function
Jianqiang Wang1, Yuanshan Han2, Fang Huang1
1Molecular Nutrition Branch, National Engineering Research Center of Rice and By-Product Deep Processing/College of Food Science and Engineering, Central South University of Forestry and Technology, Changsha, Hunan, China.
Abstract:
Diabetic foot ulcer (DFU) is a break in the skin of the foot caused by diabetes. It is one of the most serious and debilitating complications of diabetes. The previous study suggested that dominant M1 polarization during DFU could be the leading reason behind impaired wound healing. This study concluded that macrophage M1 polarization predominates in DFU skin tissue. iNOS was increased in HG-induced M1-polarized macrophages; conversely, Arg-1 was decreased. Macrophage pellets after HG stimulation can impair endothelial cell (EC) function by inhibiting cell viability, tube formation and cell migration, indicating M1 macrophage-derived small extracellular vesicles (sEVs) -mediated HUVEC dysfunction. sEVs miR-503 was significantly upregulated in response to HG stimulation, but inhibition of miR-503 in HG-stimulated macrophages attenuated M1 macrophage-induced HUVEC dysfunction. ACO1 interacted with miR-503 and mediated the miR-503 package into sEVs. Under HG stimulation, sEVs miR-503 taken in by HUVECs targeted IGF1R in HUVECs and inhibited IGF1R expression. In HUVECs, miR-503 inhibition improved HG-caused HUVEC dysfunction, whereas IGF1R knockdown aggravated HUVEC dysfunction; IGF1R knockdown partially attenuated miR-503 inhibition effects on HUVECs. In the skin wound model in control or STZ-induced diabetic mice, miR-503-inhibited sEVs improved, whereas IGF1R knockdown further hindered wound healing. Therefore, it can be inferred from the results that the M1 macrophage-derived sEVs miR-503 targets IGF1R in HUVECs, inhibits IGF1R expression, leads to HUVEC dysfunction, and impedes wound healing in diabetic patients, while packaging miR-503 as an M1 macrophage-derived sEVs may be mediated by ACO1.
Insights
Macrophage M1 polarization in diabetic foot ulcers impairs wound healing. Small extracellular vesicles carrying miR-503 from these macrophages hinder endothelial cell function and delay healing, suggesting a therapeutic target.
Area of Science:
- Cell Biology
- Immunology
- Diabetology
Background:
- Diabetic foot ulcer (DFU) is a severe complication of diabetes, often linked to impaired wound healing.
- Previous research suggests M1 macrophage polarization contributes to poor DFU healing.
- Macrophage-derived small extracellular vesicles (sEVs) are implicated in intercellular communication and disease pathogenesis.
Purpose of the Study:
- To investigate the role of M1 macrophage polarization and their derived sEVs in diabetic foot ulcer pathogenesis.
- To elucidate the specific molecular mechanisms by which M1 macrophage sEVs impair endothelial cell function and wound healing in diabetes.
- To identify potential therapeutic targets for improving DFU healing.
Main Methods:
- In vitro studies using high glucose (HG)-stimulated macrophages and human umbilical vein endothelial cells (HUVECs).
- Analysis of macrophage polarization markers (iNOS, Arg-1) and sEV cargo (miR-503).
- Assessment of endothelial cell function (viability, tube formation, migration) and gene expression (IGF1R).
- In vivo studies using a mouse model of diabetic wound healing.
Main Results:
- M1 macrophage polarization predominated in DFU tissue, with increased iNOS and decreased Arg-1.
- M1 macrophage-derived sEVs impaired HUVEC viability, tube formation, and migration.
- HG stimulation upregulated miR-503 in sEVs, and inhibiting miR-503 attenuated M1 macrophage-induced HUVEC dysfunction.
- ACO1 mediated miR-503 packaging into sEVs; miR-503 targeted and inhibited IGF1R expression in HUVECs.
- In vivo, miR-503-inhibited sEVs improved diabetic wound healing, while IGF1R knockdown worsened it.
Conclusions:
- M1 macrophage-derived sEVs, particularly miR-503, play a critical role in impairing endothelial cell function and hindering wound healing in diabetic foot ulcers.
- The miR-503/IGF1R axis is a key pathway mediating M1 macrophage-induced endothelial cell dysfunction in DFU.
- Targeting M1 macrophage-derived miR-503 represents a potential therapeutic strategy for enhancing diabetic wound healing.
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