Background

IL-33 plays an important role in the development of experimental asthma.

Objective

We sought to study the role of the IL-33 receptor suppressor of tumorigenicity 2 (ST2) in the persistence of asthma in a mouse model.

Methods

We studied allergen-induced experimental asthma in ST2 knockout (KO) and wild-type control mice. We measured airway hyperresponsiveness by using flexiVent; inflammatory indices by using ELISA, histology, and real-time PCR; and type 2 innate lymphoid cells (ILC2s) in lung single-cell preparations by using flow cytometry.

Results

Airway hyperresponsiveness was increased in allergen-treated ST2 KO mice and comparable with that in allergen-treated wild-type control mice. Peribronchial and perivascular inflammation and mucus production were largely similar in both groups. Persistence of experimental asthma in ST2 KO mice was associated with an increase in levels of thymic stromal lymphopoietin (TSLP), IL-9, and IL-13, but not IL-5, in bronchoalveolar lavage fluid. Expectedly, ST2 deletion caused a reduction in IL-13⁺ CD4 T cells, forkhead box P3–positive regulatory T cells, and IL-5⁺ ILC2s. Unexpectedly, ST2 deletion led to an overall increase in innate lymphoid cells (CD45⁺lin⁻CD25⁺ cells) and IL-13⁺ ILC2s, emergence of a TSLP receptor–positive IL-9⁺ ILC2 population, and an increase in intraepithelial mast cell numbers in the lung. An anti-TSLP antibody abrogated airway hyperresponsiveness, inflammation, and mucus production in allergen-treated ST2 KO mice. It also caused a reduction in innate lymphoid cell, ILC2, and IL-9⁺ and IL-13⁺ ILC2 numbers in the lung.

Conclusions

Genetic deletion of the IL-33 receptor paradoxically increases TSLP production, which stimulates the emergence of IL-9⁺ and IL-13⁺ ILC2s and mast cells and leads to development of chronic experimental asthma. An anti-TSLP antibody abrogates all pathologic features of asthma in this model.

中文翻译：

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由于胸腺基质淋巴细胞生成素驱动的IL-9 ⁺和IL-13 ⁺ 2型先天性淋巴样细胞亚群的出现，实验性哮喘在IL-33受体敲除小鼠中持续存在

背景

IL-33在实验性哮喘的发展中起重要作用。

客观的

我们试图研究在小鼠模型中哮喘持续性中IL-33致瘤性受体2抑制因子2（ST2）的作用。

方法

我们在ST2基因敲除（KO）和野生型对照小鼠中研究了变应原诱导的实验性哮喘。我们通过使用flexiVent测量了气道高反应性。通过ELISA，组织学和实时PCR检测炎症指标；流式细胞术检测肺单细胞制剂中的2型先天性淋巴样细胞（ILC2）。

结果

气道高反应性在过敏原治疗的ST2 KO小鼠中增加，并且与在过敏原治疗的野生型对照小鼠中相似。两组的支气管周围和血管周围炎症和粘液产生在很大程度上相似。ST2 KO小鼠中实验性哮喘的持续存在与支气管肺泡灌洗液中胸腺基质淋巴细胞生成素（TSLP），IL-9和IL-13（而非IL-5）水平升高有关。预期地，ST2缺失导致IL-13 ⁺ CD4 T细胞，叉头盒P3阳性调节性T细胞和IL-5 ⁺ ILC2s减少。出乎意料的是，ST2缺失导致先天淋巴样细胞（CD45 ⁺ lin ^- CD25 ⁺细胞）和IL-13 ⁺总体增加ILC2，TSLP受体阳性的IL-9 ⁺ ILC2群体的出现，以及肺上皮内肥大细胞数量的增加。抗TSLP抗体消除了过敏原治疗的ST2 KO小鼠的气道高反应性，炎症和粘液产生。它还导致肺中先天淋巴样细胞，ILC2以及IL-9 ⁺和IL-13 ⁺ ILC2数量减少。

结论

IL-33受体的基因缺失自相矛盾地增加了TSLP的产生，从而刺激了IL-9 ⁺和IL-13 ⁺ ILC2s和肥大细胞的出现，并导致了慢性实验性哮喘的发展。抗TSLP抗体消除了该模型中哮喘的所有病理特征。