Both Hematopoietic-Derived and Non-Hematopoietic-Derived β-Arrestin-2 Regulates Murine Allergic Airway Disease
Both Hematopoietic-Derived and Non-Hematopoietic-Derived β-Arrestin-2 Regulates Murine Allergic Airway Disease
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DOI：
10.1165/rcmb.2009-0198oc
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发表时间：
2010-09-01
影响因子：
6.4
通讯作者：
Walker, Julia K. L.
中科院分区：
文献类型：
--
作者：
Hollingsworth, John W.;Theriot, Barbara S.;Walker, Julia K. L.
过敏性哮喘是发病的主要原因以及住院的首要原因，它是一种由辅助性T细胞调控的炎症性疾病，其特征是嗜酸性粒细胞向肺部迁移，而嗜酸性粒细胞是重要的哮喘效应细胞。炎症细胞向肺部迁移除其他事件外，还需要肺部产生的炎症趋化因子的趋化因子受体转导。尽管这种疾病广泛流行，但哮喘中调节趋化因子产生和受体调节的分子机制却知之甚少。我们实验室先前的工作表明，β - 抑制蛋白 - 2在小鼠模型中正向调节过敏性气道疾病的发展，部分是通过正向调节T淋巴细胞向肺部的趋化作用。然而，β - 抑制蛋白 - 2在许多细胞类型中表达，包括其他造血细胞和肺结构细胞，它们都参与过敏性气道疾病的发展和表现。为了确定依赖β - 抑制蛋白 - 2的过敏性炎症所需要的细胞类型，我们制备了骨髓嵌合小鼠。利用卵清蛋白诱导的小鼠过敏性气道疾病模型，我们发现嵌合小鼠中嗜酸性粒细胞和淋巴细胞炎症得以恢复，此时β - 抑制蛋白 - 2仅在造血来源的细胞类型上表达。相反，气道高反应性依赖于β - 抑制蛋白 - 2在结构细胞中的表达。我们的数据表明，β - 抑制蛋白 - 2在至少两种不同细胞类型中的表达有助于过敏性气道疾病的发病机制。
Allergic asthma, a major cause of morbidity and leading cause of hospitalizations, is an inflammatory disease orchestrated by T helper cells and characterized by the lung migration of eosinophils, which are important asthma effector cells. Lung migration of inflammatory cells requires, among other events, the chemokine receptor transduction of lung-produced inflammatory chemokines. Despite the widespread prevalence of this disease, the molecular mechanisms regulating chemokine production and receptor regulation in asthma are poorly understood. Previous work from our laboratory demonstrated that beta-arrestin-2 positively regulates the development of allergic airway disease in a mouse model, partly through positive regulation of T-lymphocyte chemotaxis to the lung. However, beta-arrestin-2 is expressed in many cell types, including other hematopoietic cells and lung structural cells, which are involved in the development and manifestation of allergic airway disease. To determine the cell types required for beta-arrestin-2 dependent allergic inflammation, we generated bone marrow chimera mice. Using the ovalbumin murine model of allergic airway disease, we show that eosinophilic and lymphocytic inflammation is restored in chimeric mice, with expression of beta-arrestin-2 exclusively on hematopoietic-derived cell types. In contrast, airway hyperresponsiveness is dependent on the expression of beta-arrestin-2 in structural cells. Our data demonstrate that the expression of beta-arrestin 2 in at least two divergent cell types contributes to the pathogenesis of allergic airway disease.