Characterizing the Role of Apolipoprotein Receptors in Asthma Pathogenesis

我们已经证实载脂蛋白E通过低密度脂蛋白受体(LDLR)依赖的机制(载脂蛋白E通过低密度脂蛋白受体介导的途径对屋尘螨诱导的哮喘进行负性调节)在哮喘的气道高反应性和杯状细胞增生中发挥内源性负性调节作用。姚X，弗雷德里克森·K，于正欣，徐翔，拉加瓦查里·N，基兰·KJ，Zywicke GJ，Kwak M，Amar MJ，Remaley AT，Levine SJ。Am J Respir CRUT CARE Med。2010年7月9日，印刷前的ePub)。载脂蛋白E是由肺内巨噬细胞合成的，其作用是通过与纤毛呼吸道上皮细胞上表达的LDLRs结合而介导的。该项目将利用载脂蛋白受体基因敲除小鼠来确定其他载脂蛋白受体在调节哮喘发病机制中的作用。此外，将描述肺载脂蛋白受体调节哮喘发病机制的机制。本研究确定了(1)极低密度脂蛋白受体通过调节树突状细胞功能在过敏性哮喘中的新作用。特别是，我们已经证明，极低密度脂蛋白受体由循环中的人树突状细胞(DC)表达，并在HDM诱导的呼吸道炎症中减弱DC介导的适应性免疫反应(《免疫学杂志》2014；192：4497)和(2)载脂蛋白A-I及其受体ABCA1转运体之间的相互作用，通过抑制肺血管内皮细胞和肺泡巨噬细胞产生粒细胞集落刺激因子来减轻卵蛋白诱导的中性粒细胞炎症(Am J Respir Cell Mol Biol，2014，51：626-36)。 LRP-1是一种清道夫类型的内吞受体，与多个配体结合。我们发现LRP-1在屋尘螨(HDM)诱导的过敏性呼吸道炎症中对树突状细胞(DC)的功能起着重要的调节作用。嗜酸性粒细胞高度哮喘患者血液中的髓系树突状细胞以及HDM攻击小鼠肺中的CD11b+树突状细胞降低了LRP-1的表达。HDM冲击的LRP-1缺陷的CD11b+DC过继转移到NAVE野生型小鼠增加了HDM挑战后嗜酸粒细胞的气道炎症，(Iii)在CD11c+细胞(包括DC和肺泡巨噬细胞)中特异性缺失LRP-1的HDM攻击小鼠，可增加嗜酸性呼吸道炎症、变态反应性致敏、TH2细胞因子产生和粘液化生，以及(Iv)LRP-1缺陷的DC对HDM抗原的摄取和呈递增加。因此，这些发现证实LRP-1在HDM诱导的嗜酸性气道炎症中是DC介导的适应性免疫的一种新的负调节因子，并提示LRP-1可能调节人类2型高哮喘内型。该项目已提前发表在《过敏和临床免疫学杂志》(2017年12月21日)上，并于2018年10月以最终形式发表(JACI2018；OCT；142(4)：1066-1079.e6(don；10.1016/j.Jaci.2017.10.044)。

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).