CNRS and University, UMR7355, Molecular Immunology, Orleans, France and Institute of Infectious Disease and Molecular Medicine, University of Cape Town, RSA.
Gut. 2013 Dec;62(12):1714-23. doi: 10.1136/gutjnl-2011-301785. Epub 2012 Nov 21.
Inflammatory bowel diseases (IBD) have been intrinsically linked to a deregulated cytokine network, but novel therapeutic principles are urgently needed. Here we identify the interleukin (IL)-33 and its receptor ST2 as key negative regulators of wound healing and permeability in the colon of mice.
Expression of IL-33 and ST2 was determined by qRT-PCR, ELISA, immunohistochemistry and western-blot analysis. Wild-type and St2(-/-) mice were used in wound healing experiments and in two experimental models of IBD triggered by 2,4,6-trinitrobenzene sulphonic acid or dextran sodium sulphate (DSS). Neutralisation of ST2 was performed by using a specific blocking antibody.
Nuclear localisation and enhanced expression of IL-33 in myofibroblasts and enterocytes was linked to disease involvement independently of inflammation, while the expression of ST2 was primarily restricted to the colonic epithelia. In two experimental models of IBD, genetic ablation of ST2 significantly improved signs of colitis, while a sustained epithelial expression of the cyto-protective factor connexin-43 was observed in DSS-treated St2-deficient mice. Unexpectedly, absence of ST2 in non-hematopoietic cells was sufficient to protect against colitis. Consistently, specific inhibition of endogenous ST2-mediated signalling by treatment with neutralising antibody improved DSS-induced colitis. In addition, IL-33 treatment impaired epithelial barrier permeability in vitro and in vivo, whereas absence of ST2 enhanced wound healing response upon acute mechanical injury in the colon.
Our study unveiled a novel non-hematopoietic function of IL-33 in epithelial barrier function and wound healing. Therefore, blocking the IL-33/ST2 axis may represent an efficient therapy in IBD.
炎症性肠病（IBD）与失调的细胞因子网络密切相关，但迫切需要新的治疗原则。在这里，我们确定白细胞介素（IL）-33及其受体 ST2 是调节小鼠结肠愈合和通透性的关键负调控因子。
通过 qRT-PCR、ELISA、免疫组织化学和 Western blot 分析来确定 IL-33 和 ST2 的表达。在伤口愈合实验中和使用 2,4,6-三硝基苯磺酸或葡聚糖硫酸钠（DSS）引发的两种 IBD 实验模型中使用野生型和 St2（-/-）小鼠。通过使用特异性阻断抗体来中和 ST2。
肌成纤维细胞和肠上皮细胞中核定位和增强的 IL-33 表达与疾病的发生有关，而 ST2 的表达主要局限于结肠上皮。在两种 IBD 实验模型中，ST2 的基因缺失显著改善了结肠炎的症状，而在 DSS 处理的 St2 缺陷小鼠中观察到保护性细胞因子连接蛋白-43 的持续上皮表达。出乎意料的是，非造血细胞中 ST2 的缺失足以保护免受结肠炎的影响。一致地，用中和抗体特异性抑制内源性 ST2 介导的信号转导可改善 DSS 诱导的结肠炎。此外，IL-33 处理可损害体外和体内的上皮屏障通透性，而 ST2 的缺失可增强急性机械损伤后结肠的愈合反应。
我们的研究揭示了 IL-33 在上皮屏障功能和伤口愈合中的新型非造血细胞功能。因此，阻断 IL-33/ST2 轴可能是 IBD 的有效治疗方法。
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