Division of Genetics, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
Genes Cells. 2013 Jan;18(1):56-65. doi: 10.1111/gtc.12016. Epub 2012 Dec 4.
Asthma is a chronic inflammatory disease of the lung with airflow obstruction and bronchospasm, characterized by pulmonary eosinophilia, airway remodeling, increased airway hyperresponsiveness to environmental stimuli, and excessive Th2-type cytokine production. Recent studies indicate that crosstalk between the innate and adaptive immune systems is crucial for this disease. We and others have showed that the Dok (downstream of tyrosine kinases) family adaptors, Dok-1, Dok-2, and Dok-3, play essential roles in negative regulation of a wide variety of signaling pathways in both innate and adaptive immunities. Here, histopathology and bronchoalveolar lavage fluid (BALF) cellularity showed spontaneous pulmonary inflammation in Dok-1-/- Dok-2-/- Dok-3-/- (TKO) mice, but not in Dok-1-/- Dok-2-/- or Dok-3-/- mice, with hallmarks of asthma, including eosinophilia, goblet cell hyperplasia, and subepithelial fibrosis. Consistently, TKO mice, but not the other mutants, showed increased airway hyperresponsiveness to methacholine inhalation. In addition, Th2-type cytokine concentrations in BALF were increased in TKO mice. These findings provide strong evidence that Dok-1, Dok-2, and Dok-3 cooperatively play critical anti-inflammatory roles in lung homeostasis.
哮喘是一种慢性肺部炎症性疾病，伴有气流阻塞和支气管痉挛，其特征是肺部嗜酸性粒细胞增多、气道重塑、对环境刺激的气道高反应性增加以及过度产生 Th2 型细胞因子。最近的研究表明，先天免疫和适应性免疫系统之间的串扰对于这种疾病至关重要。我们和其他人已经表明，Dok（酪氨酸激酶下游）家族衔接蛋白 Dok-1、Dok-2 和 Dok-3 在先天免疫和适应性免疫中对多种信号通路的负调控中发挥着重要作用。在这里，组织病理学和支气管肺泡灌洗液（BALF）细胞计数显示，Dok-1-/- Dok-2-/- Dok-3-/-（TKO）小鼠会自发发生肺部炎症，但 Dok-1-/- Dok-2-/-或 Dok-3-/-小鼠不会发生哮喘的特征性变化，包括嗜酸性粒细胞增多、杯状细胞增生和上皮下纤维化。一致的是，只有 TKO 小鼠而非其他突变体表现出对乙酰甲胆碱吸入的气道高反应性增加。此外，TKO 小鼠的 BALF 中 Th2 型细胞因子浓度增加。这些发现为 Dok-1、Dok-2 和 Dok-3 协同在肺稳态中发挥关键抗炎作用提供了有力证据。
