Cui Qiaoli, Zhang Zhenming, Qin Lang, Teng Zhaolin, Wang Zhihong, Wu Wei, Fan Linling, Su Jing, Hao Yexuan, Qin Ji, Zhang Li, Wang Qi, Zhuang Yuan, Zheng Hangping, Zhang Shuo, Geng Xiang, Zhu Lei, Chen Yijian, Lu Bin, Li Yiming, Zhu Xiaoming
Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, China.
Department of Orthopaedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Diabetes Investig. 2025 Mar;16(3):405-413. doi: 10.1111/jdi.14389. Epub 2024 Dec 23.
AIMS/INTRODUCTION: Diabetic foot ulcer (DFU) is a prevalent complication of diabetes characterized by heightened inflammation and impaired wound-healing processes. Interleukin-37 (IL-37) is a natural suppressor of innate inflammation. Here, we aim to investigate the potential of IL-37 in enhancing the healing process of diabetic wounds.
The skin samples of DFU and non-diabetic patients during foot and ankle orthopedic surgery were collected. The IL-37 transgenic mice (IL-37Tg) were created using CRISPR/Cas-mediated genome engineering. Mice were administered streptozotocin (STZ, 150 mg/kg) to induce a diabetic model. After 4 weeks, an equidistant full-thickness excisional wound measuring 8 mm was created on the central back of each mouse and allowed to heal naturally. Body weight and blood glucose levels were measured weekly. The wound area was measured, and skin samples were collected on Day 10 for further Quantitative polymerase chain reaction (qPCR) and WB detection and RNA sequencing analysis.
The proinflammation cytokines such as TNF-α and IL-1β and the MAPK signaling pathway were significantly increased in the wound margin of DFU patients. Compared with diabetic mice, diabetic IL-37Tg mice showed a significantly accelerated healing process. The enriched signaling pathways in RNA sequencing included cytokine-cytokine receptor interaction, TNF signaling pathway, and NOD-like receptor signaling pathway. Through QPCR and WB detection, we found that IL-37 could inhibit the activated MAPK and NOD-like signaling pathway, reducing TNF-α, IL-1β, and NLRP3 expression in the diabetic wound.
IL-37 promotes skin wound healing in diabetic mice, providing a new possible target for treating diabetic wounds.
目的/引言：糖尿病足溃疡（DFU）是糖尿病常见的并发症，其特征为炎症加剧和伤口愈合过程受损。白细胞介素-37（IL-37）是先天性炎症的天然抑制剂。在此，我们旨在研究IL-37在促进糖尿病伤口愈合过程中的潜力。
收集足踝部骨科手术期间DFU患者和非糖尿病患者的皮肤样本。使用CRISPR/Cas介导的基因组工程创建IL-37转基因小鼠（IL-37Tg）。给小鼠注射链脲佐菌素（STZ，150mg/kg）以诱导糖尿病模型。4周后，在每只小鼠的背部中央创建一个直径8mm的等距全层切除伤口，让其自然愈合。每周测量体重和血糖水平。测量伤口面积，并在第10天收集皮肤样本用于进一步的定量聚合酶链反应（qPCR）、蛋白质免疫印迹（WB）检测和RNA测序分析。
DFU患者伤口边缘的促炎细胞因子如肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）以及丝裂原活化蛋白激酶（MAPK）信号通路显著增加。与糖尿病小鼠相比，糖尿病IL-37Tg小鼠的愈合过程明显加速。RNA测序中富集的信号通路包括细胞因子-细胞因子受体相互作用、TNF信号通路和NOD样受体信号通路。通过qPCR和WB检测，我们发现IL-37可以抑制活化的MAPK和NOD样信号通路，降低糖尿病伤口中TNF-α、IL-1β和NLRP3的表达。
IL-37促进糖尿病小鼠皮肤伤口愈合，为治疗糖尿病伤口提供了一个新的可能靶点。
