Characterizing the Role of Apolipoprotein Receptors in Asthma Pathogenesis

表征载脂蛋白受体在哮喘发病机制中的作用

基本信息

批准号：
10929121
负责人：
Stewart Levine
金额：
$ 170.73万
依托单位：
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10929121
关键词：
ATP binding cassette transporter 1 Adoptive Transfer Allergic Alveolar Macrophages Apolipoprotein A-I Apolipoprotein E Apolipoproteins Asthma Attenuated Binding Caring Cell physiology Cells Clinical Immunology Dendritic Cells Dermatophagoides Antigens Development Epithelial Cells Extrinsic asthma Goals Goblet Cells Granulocyte Colony-Stimulating Factor Human Hyperplasia Hypersensitivity ITGAM gene ITGAX gene Immunology Journals Knockout Mice Ligands Low Density Lipoprotein Receptor Lung Macrophage Mediating Metaplasia Mucous body substance Mus Myelogenous Ovalbumin Pathogenesis Pathway interactions Pharmaceutical Preparations Physiologic pulse Play Printing Production Pyroglyphidae Research Role VLDL receptor Vascular Endothelial Cell Wild Type Mouse adaptive immune response adaptive immunity airway epithelium airway hyperresponsiveness airway inflammation allergic airway inflammation asthmatic cytokine eosinophil insight neutrophil new therapeutic target novel receptor receptor binding uptake

项目摘要

We have identified that apolipoprotein E serves as an endogenous negative regulator of airway hyperreactivity and goblet cell hyperplasia in asthma by a low density lipoprotein receptor(LDLR)-dependent mechanism (Apolipoprotein E Negatively Regulates House Dust Mite-induced Asthma via a LDL Receptor-mediated Pathway. Yao X, Fredriksson K, Yu ZX, Xu X, Raghavachari N, Keeran KJ, Zywicke GJ, Kwak M, Amar MJ, Remaley AT, Levine SJ. Am J Respir Crit Care Med. 2010 Jul 9. Epub ahead of print). The effects of apoE, which is synthesized by macrophages in the lung, are mediated via binding to LDLRs that are expressed on ciliated airway epithelial cells. This project will utilize apolipoprotein receptor knock-out mice to define the role of other apolipoprotein receptors in modulating the pathogenesis of asthma. Furthermore, the mechanisms by which asthma pathogenesis is modulated by lung apolipoprotein receptors will be characterized. This research has identified (1) a novel role for the very low density lipoprotein receptor in allergic asthma by regulating dendritic cell function. In particular, we have shown that the very low density lipoprotein receptor is expressed by circulating human dendritic cells (DC) and attenuates DC-mediated adaptive immune responses in HDM-induced airway inflammation (Journal of Immunology 2014; 192: 4497) and (2) the interaction between apolipoprotein A-I and its receptor, the ABCA1 transporter, attenuates ovalbumin-induced neutrophilic airway inflammation by suppressing granulocyte colony-stimulating factor production by pulmonary vascular endothelial cells and alveolar macrophages (Am J Respir Cell Mol Biol, 2014, 51:626-36). LRP-1 is a scavenger-type endocytic receptor that binds multiple ligands. We have shown that LRP-1 plays an important role in modulating dendritic cell (DC) function during house dust mite (HDM)-induced allergic airway inflammation with the following findings: (i.) Myeloid dendritic cells from the blood of eosinophil-high asthmatics, as well as CD11b+ DCs from the lungs of HDM-challenged mice, have reduced LRP-1 expression, (ii.) the adoptive transfer of HDM-pulsed LRP-1-deficient CD11b+ DCs to nave wild-type mice increases eosinophilic airway inflammation following HDM challenges, (iii.) HDM-challenged mice with a specific deletion of LRP-1 in CD11c+ cells, which include DCs and alveolar macrophages, have increased eosinophilic airway inflammation, allergic sensitization, TH2 cytokine production, and mucous metaplasia, and (iv.) LRP-1-deficient DCs show increased uptake and presentation of HDM antigen. Thus, these findings identify LRP-1 as a novel negative regulator of DC-mediated adaptive immunity in HDM-induced eosinophilic airway inflammation and suggest that LRP-1 might modulate the type 2-high asthma endotype in humans. This project has been epublished ahead of print in the Journal of Allergy and Clinical Immunology (Dec 21,2017) and in final form in October 2018 (JACI 2018; Oct; 142(4):1066-1079.e6 (don; 10.1016/j.jaci.2017.10.044).

我们已经确定，通过低密度脂蛋白受体（LDLR）依赖性机制，载脂蛋白E是气道高反应性和杯状细胞增生的内源性负调节剂（载脂蛋白E负调节house ducks house duck诱导的lddl rik rik siD rik iDied sidied sidied sidied sidied sidied sidied sidied rik sidied sidied ya a a y a a ya a a a y a a ya a a ya a a a a a a a a a ya a a a a y a a ya a。 Yu ZX，Xu X，Raghavachari N，Keeran KJ，Zywicke GJ，Kwak M，Amar MJ，Remaley，Levine SJ。 APOE的作用是由肺中巨噬细胞合成的，是通过与在纤毛气道上皮细胞上表达的LDLR结合介导的。该项目将利用载脂蛋白受体敲除小鼠来定义其他载脂蛋白受体在调节哮喘发病机理中的作用。此外，将表征哮喘发病机理调节哮喘发病机理的机制。这项研究通过调节树突状细胞功能来确定（1）非常低密度脂蛋白受体在过敏性哮喘中的新作用。 In particular, we have shown that the very low density lipoprotein receptor is expressed by circulating human dendritic cells (DC) and attenuates DC-mediated adaptive immune responses in HDM-induced airway inflammation (Journal of Immunology 2014; 192: 4497) and (2) the interaction between apolipoprotein A-I and its receptor, the ABCA1 transporter, attenuates卵巢蛋白诱导的嗜中性粒细胞气道炎症通过抑制肺血管内皮细胞和肺泡巨噬细胞的粒细胞刺激因子的产生（AM J Respir Cell Mol Biol，2014，51：626-36）。 LRP-1是一种结合多个配体的清除型内吞受体。我们已经表明，LRP-1在房屋粉尘螨（HDM）诱导的过敏性气道炎症期间在调节树突细胞（DC）功能中起重要作用：（I。表达，（ii。）HDM脉冲LRP-1缺乏的CD11b+ DCS向Have野生型小鼠的表达转移会增加HDM挑战后的嗜酸性气道炎症（III。）HDM挑战的小鼠（III。）与CD11C+细胞中LRP-1的特定缺失，以及Alluce cys for cd11c+ Cell，以及Alluve aCHIL的dcs，以及Alluve dcs dcs dcs dcs的特定缺失，气道炎症，过敏性敏化，Th2细胞因子产生和粘液化生症以及（iv。）LRP-1缺陷DCS显示出增加HDM抗原的摄取和呈现。因此，这些发现将LRP-1鉴定为HDM诱导的嗜酸性气道炎症中DC介导的适应性免疫的新型负调节剂，并表明LRP-1可能会调节人类中2型高哮喘内型的型2型哮喘内型。该项目在《过敏和临床免疫学杂志》（2017年12月21日）和2018年10月的最终形式（JACI 2018; JACI 2018; 142（4）：1066-1079.E6（DON; 10.1016/j.jaci.2017.10.044）中发表。