Background

Eosinophils play a central role in propagation of allergic diseases, including asthma. Both recruitment and retention of eosinophils regulate pulmonary eosinophilia, but the question of whether alterations in apoptotic cell clearance by phagocytes contributes directly to resolution of allergic airway inflammation remains unexplored.

Objectives

In this study we investigated the role of the receptor tyrosine kinase Mer in mediating apoptotic eosinophil clearance and allergic airway inflammation resolution in vivo to establish whether apoptotic cell clearance directly affects the resolution of allergic airway inflammation.

Methods

Alveolar and bone marrow macrophages were used to study Mer-mediated phagocytosis of apoptotic eosinophils. Allergic airway inflammation resolution was modeled in mice by using ovalbumin. Fluorescently labeled apoptotic cells were administered intratracheally or eosinophil apoptosis was driven by administration of dexamethasone to determine apoptotic cell clearance in vivo.

Results

Inhibition or absence of Mer impaired phagocytosis of apoptotic human and mouse eosinophils by macrophages. Mer-deficient mice showed delayed resolution of ovalbumin-induced allergic airway inflammation, together with increased airway responsiveness to aerosolized methacholine, increased bronchoalveolar lavage fluid protein levels, altered cytokine production, and an excess of uncleared dying eosinophils after dexamethasone treatment. Alveolar macrophage phagocytosis was significantly Mer dependent, with the absence of Mer attenuating apoptotic cell clearance in vivo to enhance inflammation in response to apoptotic cells.

Conclusions

We demonstrate that Mer-mediated apoptotic cell clearance by phagocytes contributes to resolution of allergic airway inflammation, suggesting that augmenting apoptotic cell clearance is a potential therapeutic strategy for treating allergic airway inflammation.

中文翻译：

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Mer 介导的嗜酸性粒细胞 efferocytosis 调节过敏性气道炎症的消退

背景

嗜酸性粒细胞在包括哮喘在内的过敏性疾病的传播中起核心作用。嗜酸性粒细胞的募集和滞留均可调节肺嗜酸性粒细胞增多，但吞噬细胞对凋亡细胞清除的改变是否直接有助于缓解过敏性气道炎症的问题仍未得到探索。

目标

在这项研究中，我们研究了受体酪氨酸激酶 Mer 在体内介导凋亡嗜酸性粒细胞清除和过敏性气道炎症消退中的作用，以确定凋亡细胞清除是否直接影响过敏性气道炎症的消退。

方法

肺泡和骨髓巨噬细胞用于研究 Mer 介导的凋亡嗜酸性粒细胞的吞噬作用。通过使用卵清蛋白在小鼠中模拟过敏性气道炎症消退。气管内给予荧光标记的凋亡细胞或通过给予地塞米松驱动嗜酸性粒细胞凋亡以确定体内凋亡细胞清除率。

结果

Mer 的抑制或缺失会损害巨噬细胞对凋亡的人和小鼠嗜酸性粒细胞的吞噬作用。Mer 缺陷小鼠表现出卵清蛋白诱导的过敏性气道炎症消退延迟，同时气道对雾化乙酰甲胆碱的反应增加，支气管肺泡灌洗液蛋白水平增加，细胞因子产生改变，地塞米松治疗后未清除的垂死嗜酸性粒细胞过多。肺泡巨噬细胞吞噬作用显着依赖于 Mer，缺乏 Mer 会减弱体内凋亡细胞清除以增强对凋亡细胞的炎症反应。

结论

我们证明了吞噬细胞介导的 Mer 介导的凋亡细胞清除有助于缓解过敏性气道炎症，这表明增加凋亡细胞清除是治疗过敏性气道炎症的潜在治疗策略。