Exosomes from tannic acid-stimulated macrophages accelerate wound healing through miR-221-3p mediated fibroblasts migration by targeting CDKN1b

Tannic acid (TA) and its extraction were traditionally used for treatment of traumatic bleeding in China, and in the previous study we have demonstrated that TA could accelerate cutaneous wound healing in rats. We attempted to decipher the mechanism of TA in promoting wound healing. In this study, we found that TA could enhance the growth of macrophages and inhibit the release of inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-8 and IL-10) through inhibition of NF-κB/JNK pathway. TA activated Erk1/2 pathway, leading to increased expressions of growth factors, bFGF and HGF. Scratch study revealed that TA did not directly regulate the migration function of fibroblasts, but could indirectly enhance fibroblasts migration by the supernatant of TA-treated macrophages. Transwell study further proved that TA stimulates macrophages to secrete exosomes enriched in miR-221-3p by activating the p53 signaling pathway, and the exosomes entered into the fibroblast cytoplasm and bound to 3'UTR of target gene CDKN1b which induced decreased expression level of CDKN1b, leading to promoting fibroblast migration. This study provided new insights into how TA accelerates wound healing in the inflammatory and proliferative phases of wound healing.