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.
Scientific Research Department, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China.
Front Immunol. 2023 May 23;14:1104890. doi: 10.3389/fimmu.2023.1104890. eCollection 2023.
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.
糖尿病足溃疡（DFU）是由糖尿病引起的足部皮肤破裂。它是糖尿病最严重和使人虚弱的并发症之一。之前的研究表明，DFU 中占主导地位的 M1 极化可能是伤口愈合受损的主要原因。本研究得出结论，DFU 皮肤组织中巨噬细胞 M1 极化占主导地位。在高糖（HG）诱导的 M1 极化巨噬细胞中，iNOS 增加；相反，Arg-1 减少。HG 刺激后的巨噬细胞小球可以通过抑制细胞活力、管形成和细胞迁移来损害内皮细胞（EC）功能，表明 M1 巨噬细胞衍生的小细胞外囊泡（sEVs）介导的 HUVEC 功能障碍。HG 刺激后，miR-503 在 sEVs 中显著上调，但在 HG 刺激的巨噬细胞中抑制 miR-503 可减弱 M1 巨噬细胞诱导的 HUVEC 功能障碍。ACO1 与 miR-503 相互作用，并将 miR-503 包裹到 sEVs 中。在 HG 刺激下，HUVEC 摄取的 sEVs miR-503 靶向 HUVECs 中的 IGF1R 并抑制 IGF1R 表达。在 HUVECs 中，miR-503 抑制改善了 HG 引起的 HUVEC 功能障碍，而 IGF1R 敲低加重了 HUVEC 功能障碍；IGF1R 敲低部分减弱了 miR-503 对 HUVECs 的抑制作用。在对照或 STZ 诱导的糖尿病小鼠的皮肤伤口模型中，miR-503 抑制的 sEVs 改善了伤口愈合，而 IGF1R 敲低进一步阻碍了伤口愈合。因此，从结果可以推断，M1 巨噬细胞衍生的 sEVs miR-503 靶向 HUVECs 中的 IGF1R，抑制 IGF1R 表达，导致 HUVEC 功能障碍，并阻碍糖尿病患者的伤口愈合，而将 miR-503 包装为 M1 巨噬细胞衍生的 sEVs 可能由 ACO1 介导。
