低密度脂蛋白受体相关蛋白 1 通过抑制树突状细胞介导的适应性免疫应答来减轻屋尘螨诱导的嗜酸性气道炎症。
Low-density lipoprotein receptor-related protein 1 attenuates house dust mite-induced eosinophilic airway inflammation by suppressing dendritic cell-mediated adaptive immune responses.
机构信息
Laboratory of Asthma and Lung Inflammation, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
Flow Cytometry Core Facility, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
出版信息
J Allergy Clin Immunol. 2018 Oct;142(4):1066-1079.e6. doi: 10.1016/j.jaci.2017.10.044. Epub 2017 Dec 21.
BACKGROUND
Low-density lipoprotein receptor-related protein 1 (LRP-1) is a scavenger receptor that regulates adaptive immunity and inflammation. LRP-1 is not known to modulate the pathogenesis of allergic asthma.
OBJECTIVE
We sought to assess whether LRP-1 expression by dendritic cells (DCs) modulates adaptive immune responses in patients with house dust mite (HDM)-induced airways disease.
METHODS
LRP-1 expression on peripheral blood DCs was quantified by using flow cytometry. The role of LRP-1 in modulating HDM-induced airways disease was assessed in mice with deletion of LRP-1 in CD11c cells (Lrp1; CD11c-Cre) and by adoptive transfer of HDM-pulsed CD11b DCs from Lrp1; CD11c-Cre mice to wild-type (WT) mice.
RESULTS
Human peripheral blood myeloid DC subsets from patients with eosinophilic asthma have lower LRP-1 expression than cells from healthy nonasthmatic subjects. Similarly, LRP-1 expression by CD11b lung DCs was significantly reduced in HDM-challenged WT mice. HDM-challenged Lrp1; CD11c-Cre mice have a phenotype of increased eosinophilic airway inflammation, allergic sensitization, T2 cytokine production, and mucous cell metaplasia. The adoptive transfer of HDM-pulsed LRP-1-deficient CD11b DCs into WT mice generated a similar phenotype of enhanced eosinophilic inflammation and allergic sensitization. Furthermore, CD11b DCs in the lungs of Lrp1; CD11c-Cre mice have an increased ability to take up HDM antigen, whereas bone marrow-derived DCs display enhanced antigen presentation capabilities.
CONCLUSION
This identifies a novel role for LRP-1 as a negative regulator of DC-mediated adaptive immune responses in the setting of HDM-induced eosinophilic airway inflammation. Furthermore, the reduced LRP-1 expression by circulating myeloid DCs in patients with eosinophilic asthma suggests a possible role for LRP-1 in modulating type 2-high asthma.
背景
低密度脂蛋白受体相关蛋白 1（LRP-1）是一种清道夫受体，可调节适应性免疫和炎症。目前尚不清楚 LRP-1 是否调节过敏性哮喘的发病机制。
目的
我们旨在评估树突状细胞（DC）中的 LRP-1 表达是否调节尘螨（HDM）诱导的气道疾病中的适应性免疫反应。
方法
通过流式细胞术定量检测外周血 DC 上的 LRP-1 表达。通过在 CD11c 细胞（Lrp1; CD11c-Cre）中缺失 LRP-1 和将 HDM 脉冲 CD11b DC 从 Lrp1; CD11c-Cre 小鼠过继转移到野生型（WT）小鼠来评估 LRP-1 在调节 HDM 诱导的气道疾病中的作用。
结果
与健康非哮喘患者相比，嗜酸性哮喘患者的人外周血髓样 DC 亚群的 LRP-1 表达水平较低。同样，在 WT 小鼠接受 HDM 挑战后，CD11b 肺 DC 的 LRP-1 表达显著降低。Lrp1; CD11c-Cre 小鼠接受 HDM 挑战后，表现出嗜酸性气道炎症、过敏致敏、T2 细胞因子产生和粘液细胞化生增加的表型。将 HDM 脉冲的 LRP-1 缺陷型 CD11b DC 过继转移到 WT 小鼠中，可产生增强的嗜酸性炎症和过敏致敏的类似表型。此外，Lrp1; CD11c-Cre 小鼠肺部的 CD11b DC 摄取 HDM 抗原的能力增强，而骨髓来源的 DC 显示出增强的抗原呈递能力。
结论
这确定了 LRP-1 作为 HDM 诱导的嗜酸性气道炎症中 DC 介导的适应性免疫反应的负调节剂的新作用。此外，嗜酸性哮喘患者循环髓样 DC 中 LRP-1 的表达降低表明 LRP-1 可能在调节 2 型高哮喘中起作用。
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