MicroRNA-122-5p is upregulated in diabetic foot ulcers and decelerates the transition from the inflammatory to the proliferative stage

Abstract

BACKGROUND

Shifting from the inflammatory to the proliferative phase represents a pivotal step during managing diabetic foot ulcers (DFUs); however, existing medical interventions remain insufficient. MicroRNAs (miRs) highlight notable capacity for accelerating the repair process of DFUs. Previous research has demonstrated which miR-122-5p regulates matrix metalloproteinases under diabetic conditions, thereby influencing extracellular matrix dynamics.

AIM

To investigate the impact of miR-122-5p on the transition from the inflammatory to the proliferative stage in DFU.

METHODS

Analysis for miR-122-5p expression in skin tissues from diabetic ulcer patients and mice was analyzed using quantitative real-time polymerase chain reaction (qRT-PCR). A diabetic wound healing model induced by streptozotocin was used, with mice receiving intradermal injections of adeno-associated virus -DJ encoding empty vector or miR-122. Skin tissues were retrieved at 3, 7, and 14 days after injury for gene expression analysis, histology, immunohistochemistry, and network studies. The study explored miR-122-5p’s role in macrophage-fibroblast interactions and its effect on transitioning from inflammation to proliferation in DFU healing.

RESULTS

High-throughput sequencing revealed miR-122-5p as crucial for DFU healing. qRT-PCR showed significant upregulation of miR-122-5p within diabetic skin among DFU individuals and mice. Western blot, along with immunohistochemical and enzyme-linked immunosorbent assay, demonstrating the upregulation of inflammatory mediators (hypoxia inducible factor-1α, matrix metalloproteinase 9, tumor necrosis factor-α) and reduced fibrosis markers (fibronectin 1, α-smooth muscle actin) by targeting vascular endothelial growth factor. Fluorescence in situ hybridization indicated its expression localized to epidermal keratinocytes and fibroblasts in diabetic mice. Immunofluorescence revealed enhanced increased presence of M1 macrophages and reduced M2 polarization, highlighting its role in inflammation. MiR-122-5p elevated inflammatory cytokine levels while suppressing fibrotic activity from fibroblasts exposed to macrophage-derived media, highlighting its pivotal role in regulating DFU healing.

CONCLUSION

MiR-122-5p impedes cutaneous healing of diabetic mice via enhancing inflammation and inhibiting fibrosis, offering insights into miR roles in human skin wound repair.

Keywords: MicroRNA-122-5p; Diabetic foot ulcer; Wound healing; Inflammation; Fibrosis

Core Tip: The shift from the inflammatory to the proliferative stage is essential for effective treatment of diabetic foot ulcers (DFUs). Through bioinformatics analysis and experimental studies, we evaluated the role of microRNA (miR)-122-5p in DFU. MiR-122-5p was found to delay wound repair in DFU by disrupting re-epithelialization and intensifying inflammation throughout the healing process.