Surfactant Protein-A Protects against IL-13-Induced Inflammation in Asthma
Surfactant Protein-A Protects against IL-13-Induced Inflammation in Asthma
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DOI：
10.4049/jimmunol.1901227
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发表时间：
2020-05-15
影响因子：
4.4
通讯作者：
Kraft, Monica
中科院分区：
文献类型：
--
作者：
Francisco, Dave;Wang, Ying;Kraft, Monica
肺表面活性蛋白被认为是关键，不仅因为它们的作用，降低肺表面张力，而且在先天性宿主防御。报道显示，一些哮喘患者具有该蛋白质家族的一个成员，特别是表面活性蛋白-A（SP-A）的水平降低。我们的研究旨在确定SP-A对哮喘中关键效应细胞因子IL-13应答的贡献。我们的研究采用了用IL-13激发的SP-A充足和缺乏的动物模型，以及在IL-13激发的背景下用SP-A进行外源性治疗的哮喘参与者的原代上皮细胞。在两种模型系统中评估炎症反应和粘蛋白产生。与WT小鼠相比，我们发现，IL-13的活性显着增强SP-A（-/-）小鼠，这有显着增加中性粒细胞和嗜酸性粒细胞的招聘，粘蛋白的生产和哮喘相关的细胞因子在支气管肺泡灌洗液。同时，我们发现在IL-13激发过程中加入外源性SP-A时，哮喘相关因子在哮喘受试者的人细胞中减弱。尽管这些表型中的许多先前与STAT 6信号传导相关，但SP-A抑制小鼠和人上皮细胞中IL-13诱导的STAT 3磷酸化，而对STAT 6磷酸化几乎没有影响。此外，当STAT 3或IL-6在小鼠中被抑制时，在SP-A（-/-）小鼠中观察到的表型显著减弱。这些研究表明SP-A在哮喘中通过介导下游IL-6/STAT 3信号传导作为IL-13诱导的炎症的调节剂的新机制。
The lung surfactant proteins are recognized as critical not only for their role in lowering lung surface tension but also in innate host defense. Reports have shown that some asthmatic patients have decreased levels of one member of this protein family in particular, surfactant protein-A (SP-A). Our studies set out to determine the contribution of SP-A to the response of a key effector cytokine in asthma, IL-13. Our studies employ both animal models sufficient and deficient in SP-A challenged with IL-13 and primary epithelial cells from participants with asthma that are exogenously treated with SP-A in the context of IL-13 challenge. The inflammatory response and mucin production were assessed in both model systems. As compared with WT mice, we show that the activity of IL-13 is dramatically augmented in SP-A(-/-) mice, which have significantly increased neutrophil and eosinophil recruitment, mucin production and asthma-associated cytokines in the bronchoalveolar lavage fluid. In parallel, we show asthmaassociated factors are attenuated in human cells from asthma subjects when exogenous SP-A is added during IL-13 challenge. Although many of these phenotypes have previously been associated with STAT6 signaling, SP-A inhibited IL-13-induced STAT3 phosphorylation in mice and in human epithelial cells while having little effect on STAT6 phosphorylation. In addition, when either STAT3 or IL-6 were inhibited in mice, the phenotypes observed in SP-A(-/-) mice were significantly attenuated. These studies suggest a novel mechanism for SP-A in asthma as a modulator of IL-13-induced inflammation via mediating downstream IL-6/STAT3 signaling.