Service de Pneumologie, Faculty of Biology and Medicine, University of Lausanne, CHUV, Lausanne, Switzerland.
Allergy. 2014 Oct;69(10):1333-42. doi: 10.1111/all.12469. Epub 2014 Aug 16.
Thymic stromal lymphopoietin (TSLP) is a cytokine primarily produced by epithelial cells, which has been shown to be a potent inducer of T-helper 2 (Th2)-type responses. However, TSLP has pleiotropic effects upon immune cells, and although extensively studied in the context of atopic asthma, its relevance as a therapeutic target and its role in the pathogenesis of nonatopic asthma remains unknown. We sought to investigate the role of TSLP in atopic, nonatopic and viral-induced exacerbations of pulmonary inflammation.
Using stringently defined murine models of atopic, nonatopic and virally exacerbated forms of pulmonary inflammation, we compared inflammatory responses of C57BL/6 wild-type (WT) and TSLP receptor-deficient (TSLPR KO) mice.
Thymic stromal lymphopoietin receptor (TSLPR) signaling was crucial for the development of atopic asthma. Specifically, TSLPR signaling to lung recruited CD4+ T cells enhanced eosinophilia, goblet cell hyperplasia, and overall inflammation within the airways. In contrast, the absence of TSLPR signaling was associated with strikingly exaggerated pulmonary neutrophilic inflammation in a nonatopic model of airway inflammation. The inflammation was associated with excessive levels of interleukin (IL)-17A in the lungs, indicating that TSLP negatively regulates IL-17A. In addition, in a model of influenza-induced exacerbation of atopic airway inflammation, the absence of TSLPR signaling also led to exaggerated neutrophilic inflammation.
Thymic stromal lymphopoietin plays divergent roles in the pathogenesis of atopic and nonatopic asthma phenotypes by either enhancing Th2 responses or curtailing T-helper 17 responses. These findings raise important caveats for the design of therapeutic interventions targeting TSLP in asthma.
胸腺基质淋巴细胞生成素（TSLP）是一种主要由上皮细胞产生的细胞因子，它已被证明是 T 辅助 2（Th2）型反应的有效诱导剂。然而，TSLP 对免疫细胞具有多效性作用，尽管在特应性哮喘的背景下进行了广泛研究，但它作为治疗靶点的相关性及其在非特应性哮喘发病机制中的作用仍然未知。我们试图研究 TSLP 在特应性、非特应性和病毒诱发的肺部炎症加重中的作用。
使用严格定义的特应性、非特应性和病毒加重型肺部炎症的小鼠模型，我们比较了 C57BL/6 野生型（WT）和 TSLP 受体缺陷（TSLPR KO）小鼠的炎症反应。
TSLP 受体（TSLPR）信号对特应性哮喘的发展至关重要。具体而言，TSLPR 信号向肺部募集的 CD4+T 细胞增强了嗜酸性粒细胞增多、杯状细胞增生和气道内的总体炎症。相比之下，在非特应性气道炎症模型中，缺乏 TSLPR 信号与肺部中性粒细胞炎症的显著加剧相关。这种炎症与肺部白细胞介素（IL）-17A 水平过高有关，表明 TSLP 负调控 IL-17A。此外，在特应性气道炎症加重的流感模型中，缺乏 TSLPR 信号也导致中性粒细胞炎症加剧。
TSLP 通过增强 Th2 反应或抑制辅助性 17（Th17）反应，在特应性和非特应性哮喘表型的发病机制中发挥不同的作用。这些发现为设计针对哮喘中 TSLP 的治疗干预措施提出了重要的警示。
