Dickinson John D, Alevy Yael, Malvin Nicole P, Patel Khushbu K, Gunsten Sean P, Holtzman Michael J, Stappenbeck Thaddeus S, Brody Steven L
a Department of Medicine , Washington University , St. Louis , MO , USA.
b Department of Pathology and Immunology , Washington University , St. Louis , MO , USA.
Autophagy. 2016;12(2):397-409. doi: 10.1080/15548627.2015.1056967. Epub 2015 Jun 10.
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.
细胞因子对自噬的调节在疾病发病机制中日益受到重视，目前的观点认为1型细胞因子激活自噬，而2型细胞因子具有抑制作用。然而，这一模式主要源于对免疫细胞的研究，在包括调节免疫反应的前哨上皮细胞在内的组织细胞中却鲜有描述。特别是，2型细胞因子白细胞介素13（IL13）驱动气道杯状细胞的形成，这些细胞分泌过多黏液是气道疾病的一个特征，但这一过程是否受自噬影响尚不清楚。在这里，我们使用一种气道疾病小鼠模型，其中白细胞介素33（IL33）刺激导致气道杯状细胞的IL13依赖性形成，通过黏蛋白MUC5AC（黏蛋白5AC，寡聚黏液/凝胶形成）水平进行追踪，我们发现与野生型对照小鼠相比，自噬基因Atg16l1缺陷小鼠的这些细胞在黏液分泌方面存在障碍。同样，用IL13处理以刺激黏液形成的原代培养人气管上皮细胞，与未消耗的对照细胞相比，在自噬基因ATG5（自噬相关5）或ATG14（自噬相关14）消耗的细胞中，MUC5AC分泌也存在障碍。我们的研究结果表明，自噬在2型IL13依赖性免疫疾病过程中对气道黏液分泌至关重要，从而为减轻哮喘、慢性阻塞性肺疾病和囊性纤维化肺病等高分泌性炎症疾病中的气道阻塞提供了一种新的治疗策略。综上所述，这些观察结果表明Th2细胞因子对自噬的调节依赖于细胞环境。
