IL13 activates autophagy to regulate secretion in airway epithelial cells
IL13 activates autophagy to regulate secretion in airway epithelial cells
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DOI：
10.1080/15548627.2015.1056967
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发表时间：
2016-01-01
期刊：
影响因子：
13.3
通讯作者：
Brody, Steven L.
中科院分区：
文献类型：
--
作者：
Dickinson, John D.;Alevy, Yael;Brody, Steven L.
自噬的细胞因子调节在疾病发病机制中越来越被认识到，目前的概念表明，1型细胞因子激活自噬，而2型细胞因子是抑制性的。然而，这种模式主要来自免疫细胞的研究，并且在组织细胞中特征不佳，包括调节免疫应答的哨兵上皮细胞。特别是，2型细胞因子IL 13（白细胞介素13）驱动气道杯状细胞的形成，分泌过量粘液作为气道疾病的特征，但这一过程是否受到自噬的影响尚不清楚。在这里，我们使用了一个小鼠模型的气道疾病，其中IL 33（白细胞介素33）刺激导致IL 13依赖性形成的气道杯状细胞的粘蛋白MUC 5AC（粘蛋白5AC，寡聚体粘液/凝胶形成）的水平跟踪，我们表明，这些细胞表现出一个自噬基因Atg 16 l1缺陷的小鼠相比，野生型对照小鼠的粘液分泌阻滞。类似地，与未耗尽的对照细胞相比，用IL 13处理以刺激粘液形成的原代培养人气管上皮细胞在耗尽自噬基因ATG 5（自噬相关5）或ATG 14（自噬相关14）的细胞中也表现出MUC 5AC分泌的阻断。我们的研究结果表明，自噬是必不可少的2型，IL 13依赖性免疫疾病过程中的气道粘液分泌，从而提供了一种新的治疗策略，减轻气道阻塞的高分泌性炎症性疾病，如哮喘，慢性阻塞性肺病，囊性纤维化肺病。综上所述，这些观察结果表明Th 2细胞因子对自噬的调节是细胞环境依赖性的。
Cytokine modulation of autophagy is increasingly recognized in disease pathogenesis, and current concepts suggest that type 1 cytokines activate autophagy, whereas type 2 cytokines are inhibitory. However, this paradigm derives primarily from studies of immune cells and is poorly characterized in tissue cells, including sentinel epithelial cells that regulate the immune response. In particular, the type 2 cytokine IL13 (interleukin 13) drives the formation of airway goblet cells that secrete excess mucus as a characteristic feature of airway disease, but whether this process is influenced by autophagy was undefined. Here we use a mouse model of airway disease in which IL33 (interleukin 33) stimulation leads to IL13-dependent formation of airway goblet cells as tracked by levels of mucin MUC5AC (mucin 5AC, oligomeric mucus/gel forming), and we show that these cells manifest a block in mucus secretion in autophagy gene Atg16l1-deficient mice compared to wild-type control mice. Similarly, primary-culture human tracheal epithelial cells treated with IL13 to stimulate mucus formation also exhibit a block in MUC5AC secretion in cells depleted of autophagy gene ATG5 (autophagy-related 5) or ATG14 (autophagy-related 14) compared to nondepleted control cells. Our findings indicate that autophagy is essential for airway mucus secretion in a type 2, IL13-dependent immune disease process and thereby provide a novel therapeutic strategy for attenuating airway obstruction in hypersecretory inflammatory diseases such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis lung disease. Taken together, these observations suggest that the regulation of autophagy by Th2 cytokines is cell-context dependent.