The E3 ubiquitin ligase midline 1 promotes allergen and rhinovirus-induced asthma by inhibiting protein phosphatase 2A activity
The E3 ubiquitin ligase midline 1 promotes allergen and rhinovirus-induced asthma by inhibiting protein phosphatase 2A activity
复制标题
DOI：
10.1038/nm.3049
复制
发表时间：
2013-02-01
期刊：
影响因子：
82.9
通讯作者：
Mattes, Joerg
中科院分区：
文献类型：
--
作者：
Collison, Adam;Hatchwell, Luke;Mattes, Joerg
过敏性气道炎症与过敏原激活先天免疫途径有关。哮喘急性加重通常与鼻病毒感染有关。在这里，我们表明，暴露于屋尘螨（HDM）或鼻病毒感染后，E3泛素连接酶中线1（MID 1）在小鼠支气管上皮细胞上调。HDM以Toll样受体4（TLR 4）和肿瘤坏死因子相关凋亡诱导配体（TRAIL）依赖性方式调节TNF α表达。蛋白磷酸酶2A（PP 2A）通过与其催化亚基PP 2Ac结合而降低其活性。在暴露于HDM的小鼠中，使用不可磷酸化的FTY 720类似物的MID 1的siRNA介导的敲低或PP 2A的药理学活化降低了气道高反应性和炎症，包括白细胞介素-25（IL-25）、IL-33和CCL 20的表达、IL-5和IL-13的释放、核因子（NF）κ B活性、p38丝裂原活化蛋白激酶（MAPK）磷酸化、嗜酸性粒细胞、T淋巴细胞和髓样树突细胞的积聚，以及粘液产生细胞的数量。MID 1抑制也限制了鼻病毒引起的过敏性气道疾病的恶化。我们发现MID 1在HDM或鼻病毒暴露后在原代人支气管上皮细胞中上调，并且这与TRAIL和CCL 20表达相关。总之，这些发现确定了MID 1在过敏性气道炎症中的关键作用，并将先天免疫途径激活与哮喘的发展和恶化联系起来。
Allergic airway inflammation is associated with activation of innate immune pathways by allergens. Acute exacerbations of asthma are commonly associated with rhinovirus infection. Here we show that, after exposure to house dust mite (HDM) or rhinovirus infection, the E3 ubiquitin ligase midline 1 (MID1) is upregulated in mouse bronchial epithelium. HDM regulates MIDI expression in a Toll-like receptor 4 (TLR4)- and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent manner. MIDI decreases protein phosphatase 2A (PP2A) activity through association with its catalytic subunit PP2Ac. siRNA-mediated knockdown of MID1 or pharmacological activation of PP2A using a nonphosphorylatable FTY720 analog in mice exposed to HDM reduces airway hyperreactivity and inflammation, including the expression of interleukin-25 (IL-25), IL-33 and CCL20, IL-5 and IL-13 release, nuclear factor (NF)kappa B activity, p38 mitogen-activated protein kinase (MAPK) phosphorylation, accumulation of eosinophils, T lymphocytes and myeloid dendritic cells, and the number of mucus-producing cells. MID1 inhibition also limited rhinovirus-induced exacerbation of allergic airway disease. We found that MID1 was upregulated in primary human bronchial epithelial cells upon HDM or rhinovirus exposure, and this correlated with TRAIL and CCL20 expression. Together, these findings identify a key role of MID1 in allergic airway inflammation and links innate immune pathway activation to the development and exacerbation of asthma.