Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33.
Persistence of asthma requires multiple feedback circuits involving type 2 innate lymphoid cells and IL-33.
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DOI：
10.1016/j.jaci.2014.11.037
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发表时间：
2015-07
期刊：
影响因子：
--
通讯作者：
Alam R
中科院分区：
文献类型：
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作者：
Christianson CA;Goplen NP;Zafar I;Irvin C;Good JT Jr;Rollins DR;Gorentla B;Liu W;Gorska MM;Chu H;Martin RJ;Alam R
小鼠模型中的哮喘在停止变应原暴露后自发消退。我们开发了一种小鼠模型，在停止变应原暴露后哮喘特征持续6个月。阐明导致哮喘持续存在的因素。我们综合运用免疫学、遗传学、微阵列和药理学方法来研究哮喘持续存在的机制。在慢性哮喘小鼠中，通过抗体介导的耗竭或致死性照射消除T细胞和移植Rag 1 −/−骨髓导致气道炎症消退，但不是气道高反应性或重塑。通过致死性照射和Rag 2 −/−γc−/−骨髓移植或阻断IL 33消除T细胞和ILC 2导致气道炎症和高反应性消退。哮喘的持续需要ILC 2和上皮细胞之间的多个相互关联的反馈和前馈回路。上皮细胞IL 33诱导ILC 2，IL 13的丰富来源。后者直接诱导上皮IL 33建立正反馈回路。IL 33自动感应，产生另一个反馈回路。IL 13上调IL 33受体并促进IL 33自诱导，从而建立前馈回路。消除这些回路的任何组成部分都会导致慢性哮喘的消退。与前述一致，哮喘患者的气道中IL 33和ILC 2增加。IL 33与疾病严重程度相关。我们提出了一个关键的反馈网络和前馈上皮细胞和ILC 2之间的相互作用参与维持慢性哮喘。虽然T细胞参与了慢性哮喘的严重程度，但它们在维持气道高反应性和重塑方面是多余的。
Asthma in the mouse model spontaneously resolves after cessation of allergen exposure. We developed a mouse model where asthma features persisted for 6 months after cessation of allergen exposure. To elucidate factors contributing to the persistence of asthma. We utilized a combination of immunologic, genetic, microarray and pharmacologic approaches to dissect the mechanism of persistence of asthma. Elimination of T cells though antibody-mediated depletion or lethal irradiation and transplantation of Rag1−/− bone marrow in mice with chronic asthma resulted in resolution of airway inflammation but not airway hyperreactivity or remodeling. Elimination of T cells and ILC2 through lethal irradiation and transplantation of Rag2−/−γc−/− bone marrow or blockade of IL33 resulted in resolution of airway inflammation and hyperreactivity. Persistence of asthma required multiple interconnected feedback and feed forward circuits between ILC2 and epithelial cells. Epithelial IL33 induced ILC2, a rich source of IL13. The latter directly induced epithelial IL33 establishing a positive feedback circuit. IL33 auto-induced, generating another feedback circuit. IL13 upregulated IL33 receptors and facilitated IL33 auto-induction, thus establishing a feed forward circuit. Elimination of any component of these circuits resulted in resolution of chronic asthma. In agreement with the foregoing, IL33 and ILC2 were increased in the airways from asthmatic patients. IL33 correlated with disease severity. We present a critical network of feedback and feed forward interactions between epithelial cells and ILC2 involved in maintaining chronic asthma. Although T cells contributed to the severity of chronic asthma they were redundant in maintaining airway hyperreactivity and remodeling.