Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation
Thymic stromal lymphopoietin induces corticosteroid resistance in natural helper cells during airway inflammation
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DOI：
10.1038/ncomms3675
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发表时间：
2013-10-01
影响因子：
16.6
通讯作者：
Asano, Koichiro
中科院分区：
文献类型：
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作者：
Kabata, Hiroki;Moro, Kazuyo;Asano, Koichiro
发生在气道中并伴有杯状细胞增生和粘液产生的 2 型先天免疫反应主要由白细胞介素 33 (IL-33) 和自然辅助细胞 (NH) 驱动，后者是 2 类先天淋巴细胞 (ILC2) 的成员，也是 IL-33 的主要靶标。在这里，我们报告说，由于致敏和暴露于过敏原而引发的气道炎症，观察到皮质类固醇抵抗是通过 IL-33/NH 细胞轴诱导的。气道炎症期间合成的胸腺基质淋巴细胞生成素 (TSLP) 通过控制 NH 细胞中 STAT5 的磷酸化和 Bcl-xL 的表达，在体外和体内诱导 NH 细胞皮质类固醇抵抗中发挥关键作用。用中和抗体阻断 TSLP 或用低分子量 STAT5 抑制剂（如匹莫齐特）阻断 TSLP/STAT5 信号通路可恢复皮质类固醇敏感性。因此，TSLP-STAT5 通路可能成为严重皮质类固醇耐药性哮喘的新治疗靶点。
Type-2 innate immune responses that occur in airways and are accompanied by goblet-cell hyperplasia and mucus production are largely driven by interleukin-33 (IL-33) and natural helper (NH) cells, a member of group 2 innate lymphoid cells (ILC2s) and the major target of IL-33. Here we report that the corticosteroid resistance observed as a result of airway inflammation triggered by sensitization and exposure to allergen is induced via the IL-33/NH-cell axis. Thymic stromal lymphopoietin (TSLP) synthesized during airway inflammation plays a pivotal role in the induction of NH-cell corticosteroid resistance in vitro and in vivo, by controlling phosphorylation of STAT5 and expression of Bcl-xL in NH cells. Blockade of TSLP with a neutralizing antibody or blocking the TSLP/STAT5 signalling pathway with low molecular-weight STAT5 inhibitors such as pimozide restores corticosteroid sensitivity. Thus, the TSLP-STAT5 pathway could be a new therapeutic target in severe, corticosteroid-resistant asthma.