Zhou Kai, Yuan Lin, Liu Huijun, Du Xizi, Yao Ye, Qin Ling, Yang Ming, Xu Kun, Wu Xinyu, Wang Leyuan, Xiang Yang, Qu Xiangping, Qin Xiaoqun, Liu Chi
Department of Respiratory Medicine, National Clinical Research Center for Respiratory Diseases, Xiangya Hospital, Central South University, Xiangya Road Street, Changsha, Hunan 410078, China.
Department of Physiology, School of Basic Medicine Science, Central South University, Xiangya Road Street, Changsha, Hunan 410078, China.
J Leukoc Biol. 2023 Feb 1;113(2):216-227. doi: 10.1093/jleuko/qiac013.
Airway epithelial cells (AECs) are the first cell barrier of the respiratory system against external stimuli that play a critical role in the development of asthma. It is known that AECs play a key role in asthma susceptibility and severity. ITGB4 is a downregulated adhesion molecule in the airway epithelia of asthma patients, which was involved in the exaggerated lung inflammation after allergy stimulation. Toll-like receptor 4 (TLR4) in AECs has also been shown to play a crucial role in the development of lung inflammation in asthma patients. However, the specific intrinsic regulatory mechanism of TLR4 in AECs are still obscure. In this article, we demonstrated that ITGB4 deficiency in AECs enhances HDM-induced airway inflammation through hyperactivation of the TLR4 signaling pathway, which is mediated by inhibition of FYN phosphorylation. Moreover, TLR4-antagonist treatment or blockade of FYN can inhibit or exaggerate lung inflammation in HDM-stressed ITGB4-deficient mice, separately. Together, these results demonstrated that ITGB4 deficiency in AECs enhances HDM-induced lung inflammatory response through the ITGB4-FYN-TLR4 axis, which may provide new therapeutic approaches for the management of lung inflammation in asthma.
气道上皮细胞（AECs）是呼吸系统抵御外部刺激的第一道细胞屏障，在哮喘的发展中起关键作用。已知AECs在哮喘易感性和严重程度方面发挥关键作用。整合素β4（ITGB4）是哮喘患者气道上皮中下调的黏附分子，其参与了过敏刺激后肺部炎症的加剧。AECs中的Toll样受体4（TLR4）也已被证明在哮喘患者肺部炎症的发展中起关键作用。然而，TLR4在AECs中的具体内在调节机制仍不清楚。在本文中，我们证明AECs中ITGB4的缺乏通过TLR4信号通路的过度激活增强了屋尘螨（HDM）诱导的气道炎症，这是由FYN磷酸化的抑制介导的。此外，TLR4拮抗剂治疗或FYN阻断可分别抑制或加剧HDM应激的ITGB4缺乏小鼠的肺部炎症。总之，这些结果表明AECs中ITGB4的缺乏通过ITGB4-FYN-TLR4轴增强了HDM诱导的肺部炎症反应，这可能为哮喘肺部炎症的治疗提供新的方法。
