SAM-pointed domain ETS factor mediates epithelial cell-intrinsic innate immune signaling during airway mucous metaplasia
SAM-pointed domain ETS factor mediates epithelial cell-intrinsic innate immune signaling during airway mucous metaplasia
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DOI：
10.1073/pnas.1208092109
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发表时间：
2012-10-09
影响因子：
11.1
通讯作者：
Whitsett, Jeffrey A.
中科院分区：
文献类型：
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作者：
Korfhagen, Thomas R.;Kitzmiller, Joseph;Whitsett, Jeffrey A.
气道粘液在清除吸入的毒素、颗粒和病原体方面起着至关重要的作用。各种毒性、炎症和感染性损伤诱导气道粘液分泌和杯状细胞化生，以保持气道无菌和稳态。然而，杯状细胞化生、粘液分泌过多和气道阻塞是炎症性肺部疾病的固有特征，包括哮喘、慢性阻塞性肺病和囊性纤维化，这导致了巨大的发病率和死亡率负担。这些慢性肺部疾病因对微生物定植和反复气道感染的易感性而相互结合。这些孪生现象（粘膜化生、宿主防御受损）是否存在因果关系尚不清楚。在这里，我们证明了 SAM 指向域 ETS 因子（SPDEF）是由人原代气道细胞的鼻病毒感染诱导的，并且 SPDEF（气道杯状细胞化生的转录调节因子）的细胞质活性抑制上皮细胞的 Toll 样受体（TLR）激活。 SPDEF 与 TLR 信号转导接头 MyD88 和 TRIF 结合并抑制其活性，从而抑制 MyD88 诱导的细胞因子产生和 TRIF 诱导的干扰素 β 产生。体内气道上皮细胞中SPDEF的条件表达抑制LPS诱导的中性粒细胞浸润和细菌清除。当刺激刺激未消除时，SPDEF 介导的 TLR 和 I 型干扰素信号传导抑制可能会保护肺部免受炎症损伤。目前的研究结果至少部分地为与粘液化生相关的肺部疾病感染易感性增加提供了分子解释，以及粘液化生患者可能耐受通常与正常宿主暴发性炎症性疾病相关的微生物负荷的机制。
Airway mucus plays a critical role in clearing inhaled toxins, particles, and pathogens. Diverse toxic, inflammatory, and infectious insults induce airway mucus secretion and goblet cell metaplasia to preserve airway sterility and homeostasis. However, goblet cell metaplasia, mucus hypersecretion, and airway obstruction are integral features of inflammatory lung diseases, including asthma, chronic obstructive lung disease, and cystic fibrosis, which cause an immense burden of morbidity and mortality. These chronic lung diseases are united by susceptibility to microbial colonization and recurrent airway infections. Whether these twinned phenomena (mucous metaplasia, compromised host defenses) are causally related has been unclear. Here, we demonstrate that SAM pointed domain ETS factor (SPDEF) was induced by rhinoviral infection of primary human airway cells and that cytoplasmic activities of SPDEF, a transcriptional regulator of airway goblet cell metaplasia, inhibited Toll-like receptor (TLR) activation of epithelial cells. SPDEF bound to and inhibited activities of TLR signaling adapters, MyD88 and TRIF, inhibiting MyD88-induced cytokine production and TRIF-induced interferon beta production. Conditional expression of SPDEF in airway epithelial cells in vivo inhibited LPS-induced neutrophilic infiltration and bacterial clearance. SPDEF-mediated inhibition of both TLR and type I interferon signaling likely protects the lung against inflammatory damage when inciting stimuli are not eradicated. Present findings provide, at least in part, a molecular explanation for increased susceptibility to infection in lung diseases associated with mucous metaplasia and a mechanism by which patients with florid mucous metaplasia may tolerate microbial burdens that are usually associated with fulminant inflammatory disease in normal hosts.