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Pathogenic TH17 inflammation is sustained in the lungs by conventional dendritic cells and Toll-like receptor 4 signaling.
Journal of Allergy and Clinical Immunology ( IF 14.2 ) Pub Date : 2017-11-14 , DOI: 10.1016/j.jaci.2017.10.023
Karim H Shalaby 1 , Miranda R Lyons-Cohen 1 , Gregory S Whitehead 1 , Seddon Y Thomas 1 , Immo Prinz 2 , Hideki Nakano 1 , Donald N Cook 1
Affiliation  

BACKGROUND Mechanisms that elicit mucosal TH17 cell responses have been described, yet how these cells are sustained in chronically inflamed tissues remains unclear. OBJECTIVE We sought to understand whether maintenance of lung TH17 inflammation requires environmental agents in addition to antigen and to identify the lung antigen-presenting cell (APC) types that sustain the self-renewal of TH17 cells. METHODS Animals were exposed repeatedly to aspiration of ovalbumin alone or together with environmental adjuvants, including common house dust extract (HDE), to test their role in maintaining lung inflammation. Alternatively, antigen-specific effector/memory TH17 cells, generated in culture with CD4+ T cells from Il17a fate-mapping mice, were adoptively transferred to assess their persistence in genetically modified animals lacking distinct lung APC subsets or cell-specific Toll-like receptor (TLR) 4 signaling. TH17 cells were also cocultured with lung APC subsets to determine which of these could revive their expansion and activation. RESULTS TH17 cells and the consequent neutrophilic inflammation were poorly sustained by inhaled antigen alone but were augmented by inhalation of antigen together with HDE. This was associated with weight loss and changes in lung physiology consistent with interstitial lung disease. The effect of HDE required TLR4 signaling predominantly in lung hematopoietic cells, including CD11c+ cells. CD103+ and CD11b+ conventional dendritic cells interacted directly with TH17 cells in situ and revived the clonal expansion of TH17 cells both ex vivo and in vivo, whereas lung macrophages and B cells could not. CONCLUSION TH17-dependent inflammation in the lungs can be sustained by persistent TLR4-mediated activation of lung conventional dendritic cells.

中文翻译:

常规树突状细胞和Toll样受体4信号传导在肺部持续引起致病性TH17炎症。

背景技术已经描述了引起粘膜TH17细胞应答的机制,但是仍不清楚这些细胞如何在慢性发炎的组织中维持。目的我们试图了解维持肺TH17炎症是否还需要除抗原以外的环境因素,并确定维持TH17细胞自我更新的肺抗原呈递细胞(APC)类型。方法将动物反复单独或与环境佐剂(包括普通房屋灰尘提取物(HDE))一起吸入卵清蛋白,以测试其在维持肺部炎症中的作用。另外,抗原特异的效应子/记忆TH17细胞,是通过与来自Il17a命运映射小鼠的CD4 + T细胞培养而产生的,被过继转移以评估其在缺乏独特的肺APC亚群或细胞特异性Toll样受体(TLR)4信号传导的转基因动物中的持久性。还将TH17细胞与肺APC亚集共培养,以确定其中哪些可以恢复其扩增和激活。结果仅吸入抗原可维持TH17细胞及随后的嗜中性粒细胞炎症,但与HDE一起吸入抗原可增强TH17细胞及嗜中性粒细胞的炎症。这与体重减轻和与间质性肺疾病一致的肺生理变化有关。HDE的作用主要在包括CD11c +细胞在内的肺造血细胞中需要TLR4信号传导。CD103 +和CD11b +常规树突状细胞与原位TH17细胞直接相互作用,并能在体内外恢复TH17细胞的克隆扩增,而肺巨噬细胞和B细胞则不能。结论持久的TLR4介导的肺常规树突状细胞的活化可以维持TH17依赖性的肺部炎症。
更新日期:2017-11-14
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