Emodin accelerates diabetic wound healing by promoting anti-inflammatory macrophage polarization

Diabetic wound healing, characterized by chronic inflammation, remains a medical challenge. The failure of prompt conversion from pro-inflammatory M1-like macrophage to pro-healing M2-like macrophage is the main obstacle to diabetic wounds. Emodin, an anthraquinone derivative, has multiple bioactivities, including anti-bacterial, anticancer, and anti-inflammatory. Recently, emodin has shown potential in promoting wound heal-ing. However, the underlying molecular mechanism remains unclear. In this study, we examined the effects of emodin on wound healing in db/db diabetic mice using a full-thickness excision model. Our results showed that emodin can remarkably accelerate healing by enhancing extracellular matrix (ECM) synthesis and granulation tissue formation. We identified 32 potential targets of emodin by network pharmacology analysis, and our transcriptome analysis highlighted the down-regulation of the NF-xB signaling pathway mediated by emodin. Mechanistically, emodin was shown to inhibit the p65-NF-xB complex and promote the proportion of M2 (anti-inflammatory)-like phenotype macrophages both in vitro and vivo. Then, bone-marrow-derived macrophages were co-cultured with fibroblasts (mouse dermal fibroblasts cells). Treatment of emodin significantly increased the proportion of M2-polarized macrophages and the expression level of TGF-ll, a typical ECM formation-related cytokine secreted by the M2 macrophages in the co-cultured supernatant. We further revealed that emodin improved the proliferation of mouse dermal fibroblasts (MDFs) cells and upregulated the expression levels of collagen III, fibronectin and a-SMA in MDFs cells in emodin-treated co-culture systems. 1D11, a neutralizing antibody for all three major TGF-ll isoforms, diminished the biological effects of emodin on proliferation and ECM formation in MDFs cells. Taken together, our study suggests emodin may serve as an effective therapeutic agent for diabetic wounds.