Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital , Stockholm , Sweden.
Centre for Allergy Research, Karolinska Institutet , Stockholm , Sweden.
Am J Physiol Lung Cell Mol Physiol. 2018 Mar 1;314(3):L484-L492. doi: 10.1152/ajplung.00270.2017. Epub 2017 Nov 16.
Interleukin-33 (IL-33) and its receptor ST2 have been influentially associated with the pathophysiology of asthma. Due to the divergent roles of IL-33 in regulating mast cell functions, there is a need to further characterize IL-33/ST2-dependent mast cell responses and their significance in the context of asthma. This study aimed to investigate how IL-33/ST2-dependent mast cell responses contribute to the development of airway hyperresponsiveness (AHR) and airway inflammation in a mouse model of house dust mite (HDM)-induced asthma. Mast cell-deficient C57BL/6-Kit (Wsh) mice engrafted with either wild-type (Wsh + MC-WT) or ST2-deficient bone marrow-derived mast cells (Wsh + MC-ST2KO) were exposed to HDM delivered intranasally. An exacerbated development of AHR in response to HDM was seen in Wsh + MC-ST2KO compared with Wsh + MC-WT mice. The contribution of this IL-33/ST2-dependent mast cell response to AHR seems to reside within the smaller airways in the peripheral parts of the lung, as suggested by the isolated yet marked effect on tissue resistance. Considering the absence of a parallel increase in cellular inflammation in bronchoalveolar lavage fluid (BALF) and lung, the aggravated AHR in Wsh + MC-ST2KO mice seems to be independent of cellular inflammation. We observed an association between the elevated AHR and reduced PGE levels in BALF Due to the protective properties of PGE in airway responses, it is conceivable that IL-33/ST2-dependent mast cell induction of PGE could be responsible for the dampening effect on AHR. In conclusion, we reveal that IL-33/ST2-dependent mast cell responses can have a protective, rather than causative role, in the development of AHR.
白细胞介素-33（IL-33）及其受体 ST2 与哮喘的病理生理学密切相关。由于 IL-33 在调节肥大细胞功能方面的作用不同，因此需要进一步描述 IL-33/ST2 依赖性肥大细胞反应及其在哮喘中的意义。本研究旨在研究 IL-33/ST2 依赖性肥大细胞反应如何导致屋尘螨（HDM）诱导的哮喘小鼠模型中气道高反应性（AHR）和气道炎症的发展。用野生型（Wsh + MC-WT）或 ST2 缺陷型骨髓来源的肥大细胞（Wsh + MC-ST2KO）移植的 C57BL/6-Kit（Wsh）缺陷型肥大细胞缺乏的小鼠经鼻内暴露于 HDM。与 Wsh + MC-WT 小鼠相比，Wsh + MC-ST2KO 小鼠对 HDM 的 AHR 发展更为加剧。这种 IL-33/ST2 依赖性肥大细胞反应对 AHR 的贡献似乎位于肺外周小气道内，因为它对组织阻力有孤立但明显的影响。考虑到支气管肺泡灌洗液（BALF）和肺中细胞炎症没有平行增加，Wsh + MC-ST2KO 小鼠中加重的 AHR 似乎独立于细胞炎症。我们观察到 AHR 升高与 BALF 中 PGE 水平降低之间存在关联。由于 PGE 在气道反应中的保护特性，可以想象 IL-33/ST2 依赖性肥大细胞诱导的 PGE 可能对 AHR 产生抑制作用。总之，我们揭示 IL-33/ST2 依赖性肥大细胞反应在 AHR 的发展中可能具有保护作用，而不是致病作用。
