Gao Ruikang, Zhou Peng, Li YiQing, Li Qin
Huazhong University of Science and Technology Tongji Medical College First Clinical College: Wuhan Union Hospital, Wuhan, China.
J Cell Commun Signal. 2023 Sep;17(3):1023-1038. doi: 10.1007/s12079-023-00754-x. Epub 2023 May 22.
It is widely acknowledged that diabetes leads to slow wound healing and ulceration, and severe serious diabetic foot ulceration may result in amputation. In recent years, much emphasis has been placed on exploring diabetic wound healing to protect patients from adverse events. We recently found interleukin-7 (IL-7), a growth factor for B-cells and T-cells, and its receptor was significantly upregulated in high glucose-induced fibroblasts and skin of diabetic mice. Moreover, IL-7 stimulated fibroblasts secreted ANGPTL4, which inhibited angiogenesis of endothelial cells resulting in delayed wound healing. In our previous study, fibroblasts, endothelial cells and keratinocytes were exposed to normal glucose (5.5 mM) or high glucose (30 mM) medium for 24 h, and RNA sequencing showed that IL-7 and IL-7R were significantly upregulated in fibroblasts. To remove the effect of high glucose and explore the influence of IL-7, exogenous rMuIL-7 used to treat normal mice led to delayed wound healing by inhibiting angiogenesis. Vitro experiments revealed that IL-7-induced fibroblasts inhibited endothelial cell proliferation, migration and angiogenesis. Further experiments showed that fibroblast angiopoietin-like-4 (ANGPTL4) secretion exhibited the inhibitory effect which was blocked by culture with the corresponding neutralizing antibody. Overall, our study revealed signaling pathways associated with diabetic wound healing and provided the foothold for further studies on delayed wound healing in this patient population. Mechanism that high glucose activates IL-7-IL-7R-ANGPTL4 signal pathway in delayed wound healing. High glucose upregulates IL-7 and IL-7R in dermal fibroblasts. IL-7 stimulates dermal fibroblasts secreting Angptl4 which inhibits proliferation, migration and angiogenesis of endothelial cells in a paracrine way.
众所周知，糖尿病会导致伤口愈合缓慢和溃疡形成，严重的糖尿病足溃疡可能会导致截肢。近年来，人们非常重视探索糖尿病伤口愈合情况，以保护患者免受不良事件的影响。我们最近发现，作为B细胞和T细胞的生长因子，白细胞介素-7（IL-7）及其受体在高糖诱导的糖尿病小鼠成纤维细胞和皮肤中显著上调。此外，IL-7刺激成纤维细胞分泌血管生成素样4（ANGPTL4），其抑制内皮细胞的血管生成，导致伤口愈合延迟。在我们之前的研究中，将成纤维细胞、内皮细胞和角质形成细胞置于正常葡萄糖（5.5 mM）或高糖（30 mM）培养基中培养24小时，RNA测序显示成纤维细胞中IL-7和IL-7R显著上调。为了消除高糖的影响并探究IL-7的作用，用外源性重组鼠IL-7治疗正常小鼠会通过抑制血管生成导致伤口愈合延迟。体外实验表明，IL-7诱导的成纤维细胞抑制内皮细胞的增殖、迁移和血管生成。进一步的实验表明，成纤维细胞血管生成素样4（ANGPTL4）的分泌表现出抑制作用，而用相应的中和抗体培养可阻断这种抑制作用。总体而言，我们的研究揭示了与糖尿病伤口愈合相关的信号通路，并为该患者群体伤口愈合延迟的进一步研究提供了立足点。高糖在延迟伤口愈合中激活IL-7-IL-7R-ANGPTL4信号通路的机制。高糖上调真皮成纤维细胞中的IL-7和IL-7R。IL-7刺激真皮成纤维细胞分泌Angptl4，其以旁分泌方式抑制内皮细胞的增殖、迁移和血管生成。
