Inactivation of the interleukin-22 pathway in the airways of cystic fibrosis patients
Inactivation of the interleukin-22 pathway in the airways of cystic fibrosis patients
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DOI：
10.1016/j.cyto.2018.10.015
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发表时间：
2019-01-01
期刊：
影响因子：
3.8
通讯作者：
Si-Tahar, Mustapha
中科院分区：
文献类型：
--
作者：
Guillon, Antoine;Brea, Deborah;Si-Tahar, Mustapha
白介素22在调节粘膜屏障的维持中起着关键作用。由于囊性纤维化的气道上皮再生异常，我们研究了囊性纤维化中IL-22的完整性。我们首先用IL-22-/-小鼠证明了IL-22对于预防由铜绿假单胞菌引起的肺损伤很重要。其次，发现IL-22受体在CF患者的呼吸道上皮细胞表面正常表达。在伤口愈合试验中，经IL-22处理的CF培养物比对照组有更高的伤口闭合率，这表明IL-22信号本身在CF环境中可能起作用。然而，中性粒细胞衍生的丝氨酸蛋白酶的持久性是CF呼吸道的一个主要特征。值得注意的是，在这种富含蛋白酶的炎症微环境中，IL-22被发现发生了变化；丝氨酸蛋白酶-3最容易完全降解IL-22。因此，我们怀疑，由于IL-22被周围的中性粒细胞丝氨酸蛋白酶裂解，CF患者的肺中存在IL-22途径的获得性缺陷。
Interleukin (IL)-22 plays a critical role in regulating the maintenance of the mucosal barrier. As airway epithelial regeneration is abnormal in cystic fibrosis (CF), we investigated IL-22 integrity in CF. We first demonstrated, using Il-22-/- mice, that IL-22 is important to prevent lung damage induced by the CF pathogen Pseudomonas aeruginosa. Next, IL-22 receptor was found normally expressed at the airway epithelial surfaces of CF patients. In wound-healing assays, IL-22-treated CF cultures had higher wound-closure rate than controls, suggesting that IL 22 signaling per se could be functional in a CF context. However, persistence of neutrophil-derived serine-proteases is a major feature of CF airways. Remarkably, IL-22 was found altered in this protease-rich inflammatory microenvironment; the serine protease-3 being the most prone to fully degrade IL-22. Consequently, we suspect an acquired deficiency of the IL-22 pathway in the lungs of CF patients due to IL-22 cleavage by the surrounding neutrophil serine-proteases.