The interleukin-33 receptor ST2 is important for the development of peripheral airway hyperresponsiveness and inflammation in a house dust mite mouse model of asthma
The interleukin-33 receptor ST2 is important for the development of peripheral airway hyperresponsiveness and inflammation in a house dust mite mouse model of asthma
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DOI：
10.1111/cea.12683
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发表时间：
2016-03-01
影响因子：
6.1
通讯作者：
Nilsson, G. P.
中科院分区：
文献类型：
--
作者：
Zoltowska, A. M.;Lei, Y.;Nilsson, G. P.
研究背景IL-33及其受体ST-2在哮喘发病中的作用已被临床和实验研究证实。目的探讨IL-33/ST 2信号通路在过敏性哮喘气道高反应性（AHR）、气道炎症、气道炎症反应中的作用，哮喘小鼠模型中抗原特异性IgE的产生和肥大细胞活性。c小鼠在6周内给予屋尘螨（HDM）提取物。最后一次HDM给药后48小时，评价肺功能和气道炎症。在中心气道和外周肺中测定气道反应性。定量支气管肺泡灌洗液（BALF）中的细胞浸润和肥大细胞蛋白酶mMCP-1水平。结果ST2缺乏可降低HDM诱导的外周肺AHR，但对中心气道AHR无影响。ST2（-/-）小鼠中对HDM的炎症反应也减少，这反映在HDM特异性血清IgE的诱导降低、HDM诱导的嗜酸性粒细胞增多的抑制和BALF中巨噬细胞计数的减少以及炎症细胞流入的减少和外周气道周围杯状细胞增生的减少。此外，与野生型对照组相比，HDM处理的ST2（-/-）小鼠中炎性细胞因子IL-1、IL-5、IL-13、IL-33、GM-CSF、胸腺基质淋巴细胞生成素和肥大细胞蛋白酶mMCP-1的水平降低。我们现在提出IL-33/ST 2途径在诱导外周炎症和粘液产生中的作用，所述外周炎症和粘液产生导致外周肺中的AHR。由于哮喘被认为是一种小气道疾病，这种在肺远端诱导AHR的机制可能具有特殊的重要性。
BackgroundSeveral clinical and experimental studies have implicated IL-33 and its receptor ST2 in the development of asthma. However, the effect of IL-33/ST2 signalling on airway responses and inflammation in allergic asthma is not well established.ObjectiveTo investigate the role of IL-33/ST2 signalling in promoting allergen-induced airway hyperresponsiveness (AHR), airway inflammation, antigen-specific IgE production and mast cell activity in a mouse model of asthma.MethodsST2-deficient (ST2(-/-)) mice and control BALB/c mice were given house dust mite (HDM) extract over a 6-week period. Forty-eight hours after the final HDM administration, lung function and airway inflammation were evaluated. Airway responsiveness was determined in the central airways and peripheral lung. Cellular infiltration and mast cell protease mMCP-1 levels were quantified in bronchoalveolar lavage fluid (BALF). Recruitment of inflammatory cells and inflammatory cytokine profiles were assessed in pulmonary tissue, and HDM-specific IgE was measured in serum.ResultsST2 deficiency diminished HDM-induced AHR in the peripheral lung, while AHR in the central airways was unaffected. Inflammatory responses to HDM were also reduced in ST2(-/-) mice as reflected by the lower induction of HDM-specific serum IgE, inhibition of HDM-induced eosinophilia and reduced macrophage count in BALF, and a diminished influx of inflammatory cells and reduced goblet cell hyperplasia around the peripheral airways. Furthermore, the levels of the inflammatory cytokines IL-1, IL-5, IL-13, IL-33, GM-CSF, thymic stromal lymphopoietin and mast cell protease mMCP-1 were reduced in HDM-treated ST2(-/-) mice compared with wild-type controls.ConclusionsIn addition to promoting Th2 inflammation, we now suggest a role for the IL-33/ST2 pathway for the induction of peripheral inflammation and mucus production that causes AHR in the peripheral lung. This mechanism for inducing AHR at distal parts of the lung may be of specific importance as asthma is considered as a small airway disease.