Experimental and Translational Respiratory Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
Nat Med. 2013 Feb;19(2):232-7. doi: 10.1038/nm.3049. Epub 2013 Jan 20.
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 MID1 expression in a Toll-like receptor 4 (TLR4)- and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent manner. MID1 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)κB 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.
变应性气道炎症与过敏原激活先天免疫途径有关。哮喘的急性加重通常与鼻病毒感染有关。在这里，我们表明，在暴露于屋尘螨（HDM）或鼻病毒感染后，中线上 1 号（MID1）E3 泛素连接酶在小鼠支气管上皮细胞中上调。HDM 通过 Toll 样受体 4（TLR4）和肿瘤坏死因子相关凋亡诱导配体（TRAIL）依赖的方式调节 MID1 的表达。MID1 通过与催化亚基 PP2Ac 结合来降低蛋白磷酸酶 2A（PP2A）的活性。在暴露于 HDM 的小鼠中，使用非磷酸化的 FTY720 类似物通过 siRNA 介导的 MID1 敲低或药理学激活 PP2A，可降低气道高反应性和炎症，包括白细胞介素-25（IL-25）、白细胞介素-33 和 CCL20、IL-5 和 IL-13 的释放、核因子（NF）κB 活性、p38 丝裂原激活蛋白激酶（MAPK）磷酸化、嗜酸性粒细胞、T 淋巴细胞和髓样树突状细胞的积累以及产生粘液的细胞数量。MID1 抑制也限制了鼻病毒引起的变应性气道疾病恶化。我们发现，在 HDM 或鼻病毒暴露后，原代人支气管上皮细胞中 MID1 上调，这与 TRAIL 和 CCL20 的表达相关。总之，这些发现确定了 MID1 在变应性气道炎症中的关键作用，并将先天免疫途径的激活与哮喘的发生和恶化联系起来。
