Abstract
Diabetic wounds are recalcitrant to healing. One of the important characteristics of diabetic trauma is impaired macrophage polarization with an excessive inflammatory response. Many studies have described the important regulatory roles of microRNAs (miRNAs) in macrophage differentiation and polarization. However, the differentially expressed miRNAs involved in wound healing and their effects on diabetic wounds remain to be further explored. In this study, we first identified differentially expressed miRNAs in the inflammation, tissue formation and reconstruction phases in wound healing using Illumina sequencing and RT-qPCR techniques. Thereafter, the expression of musculus (mmu)-miR-145a-5p (“miR-145a-5p” for short) in excisional wounds of diabetic mice was identified. Finally, expression of miR-145a-5p was measured to determine its effects on macrophage polarization in murine RAW 264.7 macrophage cells and wound healing in diabetic mice. We identified differentially expressed miRNAs at different stages of wound healing, ten of which were further confirmed by RT-qPCR. Expression of miR-145a-5p in diabetic wounds was downregulated during the tissue formation stage. Furthermore, we observed that miR-145a-5p blocked M1 macrophage polarization while promoting M2 phenotype activation in vitro. Administration of miR-145a-5p mimics during initiation of the repair phase significantly accelerated wound healing in db/db diabetic mice. In conclusion, our findings suggest that rectifying macrophage function using miR-145a-5p overexpression accelerates diabetic chronic wound healing.
Highlights
Wound healing is a complex process involving a variety of cell types and the coordination of various cytokines to regulate wound repair
These results suggest that miRNAs participate in the regulation of different stages of wound healing and might be potential therapeutic targets in diseases related to abnormal wound repair
An extended inflammatory phase stemming from macrophage functional disturbance halts this progression [21, 22]
Summary
Wound healing is a complex process involving a variety of cell types and the coordination of various cytokines to regulate wound repair. Macrophages tightly participate in and regulate the entire process of wound healing, and their numbers increase during the inflammation phase, peak during the tissue formation phase, and gradually decline during the maturation phase [1, 2]. Diabetic patients experience wounds characterized by mmu-miR-145a-5p Regulates Macrophage Polarization a prolonged inflammatory state, with overactivated M1-like macrophages and elevated levels of proinflammatory factors with inadequately activated M2 phenotypes and impaired expression of growth factors [3, 4]. Because macrophages are an important target for the treatment of chronic diabetic wounds, studying the regulation of macrophage polarization may uncover therapeutic avenues to accelerate wound repair in diabetes
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