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弱屋尘螨诱导的嗜酸性气道炎症
2018/03/05
摘要
背景：低密度脂蛋白受体相关蛋白1（LRP-1）是一种调节适应性免疫应答和炎症反应的清道夫受体。LRP-1调节变应性哮喘的发病机理尚不清楚。
目的：我们试图在房尘螨（HDM）诱导的呼吸道疾病患者中评估树突状细胞（DC）表达的LRP-1是否调节适应性免疫应答。
方法：使用流式细胞术定量外周血树突状细胞的LRP-1表达。在CD11c+ 细胞中LRP-1(Lrp1fl/fl; CD11c-Cre)敲除小鼠中评估LRP-1在调节HDM-诱导的气道疾病中的作用，敲除方法为HDM激发的 CD11b+ 树突状细胞从Lrp1fl/fl; CD11c-Cre小鼠到野生型（WT）小鼠的过继转移。
结果：来自嗜酸性粒细胞性哮喘患者的人外周血液髓系DC亚群比来自健康非哮喘受试者的细胞具有更低的LRP-1表达。类似地，HDM激发的WT小鼠中CD11b+肺DC的LRP-1表达显著降低。HDM激发的Lrp1fl/fl; CD11c-Cre小鼠具有嗜酸性气道炎症、变应性致敏、TH2细胞因子产生和粘液细胞化生增加的表型。将HDM激发的LRP-1缺陷型CD11b+ DCs过继转移到WT小鼠中产生了嗜酸性粒细胞炎症和过敏性致敏增强的类似表型。此外，Lrp1fl/fl; CD11c-Cre小鼠肺中的CD11b+ DCs摄取HDM抗原的能力增强，而骨髓衍生的DC抗原呈递能力增强。
结论：这确定了LRP-1在HDM诱导的嗜酸性粒细胞性气道炎症背景中作为DC介导的适应性免疫应答的负调节因子的新作用。此外，在嗜酸性粒细胞性哮喘患者中，循环的髓样DC的LRP-1表达降低表明LRP-1在调节2型高度哮喘中可能发挥作用。
Low-density lipoprotein receptor-related protein 1 attenuates house dust mite-inducedeosinophilic airway inflammation by suppressing dendritic cell-mediated adaptive immuneresponses.
Mishra A, Yao X, Saxena A, Gordon EM, Kaler M, Cuento RA, Barochia AV, Dagur PK, McCoy JP, Keeran KJ, Jeffries KR, Qu X, Yu ZX, Levine SJ.
Abstract
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 (Lrp1fl/fl; CD11c-Cre) and by adoptive transfer of HDM-pulsed CD11b+ DCs from Lrp1fl/fl; 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 Lrp1fl/fl; CD11c-Cre mice have a phenotype of increased eosinophilic airway inflammation, allergic sensitization, TH2 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 Lrp1fl/fl; 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）是一种调节适应性免疫应答和炎症反应的清道夫受体。LRP-1调节变应性哮喘的发病机理尚不清楚。
目的：我们试图在房尘螨（HDM）诱导的呼吸道疾病患者中评估树突状细胞（DC）表达的LRP-1是否调节适应性免疫应答。
方法：使用流式细胞术定量外周血树突状细胞的LRP-1表达。在CD11c+ 细胞中LRP-1(Lrp1fl/fl; CD11c-Cre)敲除小鼠中评估LRP-1在调节HDM-诱导的气道疾病中的作用，敲除方法为HDM激发的 CD11b+ 树突状细胞从Lrp1fl/fl; CD11c-Cre小鼠到野生型（WT）小鼠的过继转移。
结果：来自嗜酸性粒细胞性哮喘患者的人外周血液髓系DC亚群比来自健康非哮喘受试者的细胞具有更低的LRP-1表达。类似地，HDM激发的WT小鼠中CD11b+肺DC的LRP-1表达显著降低。HDM激发的Lrp1fl/fl; CD11c-Cre小鼠具有嗜酸性气道炎症、变应性致敏、TH2细胞因子产生和粘液细胞化生增加的表型。将HDM激发的LRP-1缺陷型CD11b+ DCs过继转移到WT小鼠中产生了嗜酸性粒细胞炎症和过敏性致敏增强的类似表型。此外，Lrp1fl/fl; CD11c-Cre小鼠肺中的CD11b+ DCs摄取HDM抗原的能力增强，而骨髓衍生的DC抗原呈递能力增强。
结论：这确定了LRP-1在HDM诱导的嗜酸性粒细胞性气道炎症背景中作为DC介导的适应性免疫应答的负调节因子的新作用。此外，在嗜酸性粒细胞性哮喘患者中，循环的髓样DC的LRP-1表达降低表明LRP-1在调节2型高度哮喘中可能发挥作用。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(J Allergy Clin Immunol. 2017 Dec 21. pii: S0091-6749(17)32923-8.)
(J Allergy Clin Immunol. 2017 Dec 21. pii: S0091-6749(17)32923-8.)
Low-density lipoprotein receptor-related protein 1 attenuates house dust mite-inducedeosinophilic airway inflammation by suppressing dendritic cell-mediated adaptive immuneresponses.
Mishra A, Yao X, Saxena A, Gordon EM, Kaler M, Cuento RA, Barochia AV, Dagur PK, McCoy JP, Keeran KJ, Jeffries KR, Qu X, Yu ZX, Levine SJ.
Abstract
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 (Lrp1fl/fl; CD11c-Cre) and by adoptive transfer of HDM-pulsed CD11b+ DCs from Lrp1fl/fl; 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 Lrp1fl/fl; CD11c-Cre mice have a phenotype of increased eosinophilic airway inflammation, allergic sensitization, TH2 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 Lrp1fl/fl; 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.
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关于哮喘气道炎症的解决途径
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