Diabetic macrophage small extracellular vesicles-associated miR-503/IGF1R axis regulates endothelial cell function and affects wound healing

Jianqiang Wang; Yuanshan Han; Fang Huang; Liuhuan Tang; Jianfei Mu; Ying Liang

doi:10.3389/fimmu.2023.1104890

Diabetic macrophage small extracellular vesicles-associated miR-503/IGF1R axis regulates endothelial cell function and affects wound healing

Front Immunol. 2023 May 23:14:1104890. doi: 10.3389/fimmu.2023.1104890. eCollection 2023.

Authors

Jianqiang Wang¹, Yuanshan Han², Fang Huang¹, Liuhuan Tang¹, Jianfei Mu¹, Ying Liang¹

Affiliations

¹ Molecular 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.
² Scientific Research Department, The First Hospital of Hunan University of Chinese Medicine, 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.

Keywords: IGF1R; diabetic foot ulcer (DFU); endothelial cell (EC); macrophage M1 polarization; miR-503; small extracellular vesicles (sEVs).

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Diabetes Mellitus, Experimental* / complications
Diabetic Foot* / metabolism
Endothelial Cells / metabolism
Extracellular Vesicles* / metabolism
Macrophages / metabolism
Mice
MicroRNAs* / metabolism
Wound Healing

Substances

MicroRNAs

Grants and funding

This work was supported by funding from the Natural Science Foundation for Distinguished Young Scholars of Hunan Province (No. 2021JJ10078), Science and Technology Innovation Talent Project of Hunan Province (Grant No. 2022RC3056), National Key Research and Development Program of China (2022YFF1100203), Hunan Furong Scholars Program, the National Natural Science Foundation of China (No.82104846).