Tao Li, Wu Shu, Wang Qian, Xi Zhiliang, Zou Ying, Cao Mibu, Liang Kaixin, Xu Waner, Hu Qian, Ge Yuanlong, Yin Zhinan, Ju Zhenyu, Liu Zhong
Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
The Biomedical Translational Research Institute, Faculty of Medical Science, Jinan University, Guangzhou 510632, China.
Int Immunopharmacol. 2025 May 16;155:114575. doi: 10.1016/j.intimp.2025.114575. Epub 2025 Apr 10.
Diabetic foot ulcer (DFU), a serious complication of diabetes, is a life-threatening disease that often leads to lower limb amputation and a shortened lifespan. Interleukin-27 (IL-27) is a member of the IL-12 family and has the potential to exert dual effects on the immune response. The role of IL-27 in diabetic skin wound healing is unknown. The aim of this study was to investigate whether there is abnormal expression of IL-27 in diabetic skin and whether supplementation with IL-27 can promote diabetic wound healing by modulating macrophage polarization. We established a streptozotocin (STZ)-induced diabetic mouse model and constructed diabetic wounds. We assessed protein expression by western blotting (WB) and immunohistochemical (IHC) staining. We also performed hematoxylin-eosin (H&E) staining and Masson's trichrome staining. In the presence of lipopolysaccharide (LPS) and high glucose (HG), we treated the mononuclear macrophage line RAW264.7 and bone marrow-derived macrophages (BMDMs) with IL-27. To assess macrophage polarization, we examined the expression of inducible nitric oxide synthase (iNOS), IL-1β and arginase-1 (Arg-1). To understand the underlying mechanisms, we used macrophage IL-27ra knockout mice to knockout macrophage IL-27 receptors. Our in vivo experiments revealed that the expression of IL-27 in the skin of diabetic mice was significantly decreased and that supplementation with IL-27 promoted diabetic wound healing. In vitro, compared with the LPS group, supplementation with IL-27 alleviated the suppression of multiple cellular functions, such as iNOS and IL-1β expression, cell migration, and phagocytosis, in macrophages after HG exposure. Mechanistically, we found that IL-27 expression was decreased and that the activation of signal transducer and activator of transcription 3 (STAT3) by phosphorylation was inhibited in diabetic skin, leading to an inability of wound macrophages to polarize to an M1 phenotype effectively, which in turn blocked M1-to-M2 polarization of wound macrophages and ultimately delayed wound healing. The present study revealed that supplementation with IL-27 promoted M1-to-M2 polarization of wound macrophages and diabetic wound healing through the IL-27-IL-27Rα-p-STAT3 axis. These findings suggest that IL-27 may be a potential therapeutic target for DFU.
糖尿病足溃疡（DFU）是糖尿病的一种严重并发症，是一种危及生命的疾病，常导致下肢截肢和寿命缩短。白细胞介素-27（IL-27）是IL-12家族的成员，对免疫反应具有潜在的双重作用。IL-27在糖尿病皮肤伤口愈合中的作用尚不清楚。本研究的目的是调查糖尿病皮肤中IL-27是否存在异常表达，以及补充IL-27是否能通过调节巨噬细胞极化促进糖尿病伤口愈合。我们建立了链脲佐菌素（STZ）诱导的糖尿病小鼠模型并构建了糖尿病伤口。我们通过蛋白质印迹法（WB）和免疫组织化学（IHC）染色评估蛋白质表达。我们还进行了苏木精-伊红（H&E）染色和Masson三色染色。在脂多糖（LPS）和高糖（HG）存在的情况下，我们用IL-27处理单核巨噬细胞系RAW264.7和骨髓来源的巨噬细胞（BMDM）。为了评估巨噬细胞极化，我们检测了诱导型一氧化氮合酶（iNOS）、IL-1β和精氨酸酶-1（Arg-1）的表达。为了了解潜在机制，我们使用巨噬细胞IL-27ra基因敲除小鼠敲除巨噬细胞IL-27受体。我们的体内实验表明，糖尿病小鼠皮肤中IL-27的表达显著降低，补充IL-27可促进糖尿病伤口愈合。在体外，与LPS组相比，补充IL-27减轻了HG暴露后巨噬细胞中多种细胞功能的抑制，如iNOS和IL-1β表达、细胞迁移和吞噬作用。机制上，我们发现糖尿病皮肤中IL-27表达降低，磷酸化激活的信号转导和转录激活因子3（STAT3）受到抑制，导致伤口巨噬细胞无法有效极化为M1表型，进而阻断伤口巨噬细胞从M1向M2的极化，最终延迟伤口愈合。本研究表明，补充IL-27通过IL-27-IL-27Rα-p-STAT3轴促进伤口巨噬细胞从M1向M2的极化和糖尿病伤口愈合。这些发现表明，IL-27可能是DFU的一个潜在治疗靶点。
