STAT5 诱导的 Th2 发育中的疯狂发夹改变了呼吸道合胞病毒加重的气道过敏性疾病中 Delta-like 4 介导的 Th2 细胞因子产生。

STAT5-induced lunatic fringe during Th2 development alters delta-like 4-mediated Th2 cytokine production in respiratory syncytial virus-exacerbated airway allergic disease.

机构信息

Department of Pathology, University of Michigan, Ann Arbor, MI 48109;

出版信息

J Immunol. 2014 Feb 1;192(3):996-1003. doi: 10.4049/jimmunol.1301991. Epub 2013 Dec 23.

DOI:10.4049/jimmunol.1301991

PMID:24367028

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3946958/

Abstract

Notch activation plays an important role in T cell development and mature T cell differentiation. In this study, we investigated the role of Notch activation in a mouse model of respiratory syncytial virus (RSV)-exacerbated allergic airway disease. During RSV exacerbation, in vivo neutralization of a specific Notch ligand, Delta-like ligand (Dll)-4, significantly decreased airway hyperreactivity, mucus production, and Th2 cytokines. Lunatic Fringe (Lfng), a glycosyltransferase that enhances Notch activation by Dll4, was increased during RSV exacerbation. Lfng loss of function in Th2-skewed cells inhibited Dll4-Notch activation and subsequent IL-4 production. Further knockdown of Lfng in T cells in CD4Cre(+)Lfng(fl/fl) mice showed reduced Th2 response and disease pathology during RSV exacerbation. Finally, we identified STAT5-binding cis-acting regulatory element activation as a critical driver of Lfng transcriptional activation. These data demonstrate that STAT5-dependent amplification of Notch-modifying Lfng augments Th2 response via Dll4 and is critical for amplifying viral exacerbation during allergic airway disease.

摘要

Notch 激活在 T 细胞发育和成熟 T 细胞分化中发挥重要作用。在这项研究中，我们研究了 Notch 激活在呼吸道合胞病毒 (RSV)-加重的过敏性气道疾病小鼠模型中的作用。在 RSV 加重期间，体内中和特定的 Notch 配体 Delta-like 配体 (Dll)-4，可显著降低气道高反应性、粘液产生和 Th2 细胞因子。在 RSV 加重期间，狂放 Fringe（Lfng），一种增强 Dll4 激活 Notch 的糖基转移酶，增加。在 Th2 偏向细胞中敲除 Lfng 可抑制 Dll4-Notch 激活和随后的 IL-4 产生。在 CD4Cre(+)Lfng(fl/fl) 小鼠的 T 细胞中进一步敲低 Lfng 显示 RSV 加重期间 Th2 反应和疾病病理学减少。最后，我们确定 STAT5 结合顺式作用调节元件激活是 Lfng 转录激活的关键驱动因素。这些数据表明，STAT5 依赖性 Notch 修饰 Lfng 的扩增通过 Dll4 增强了 Th2 反应，并且对于过敏性气道疾病期间增强病毒加重至关重要。