Functional role of RANTES and its receptors CCR3 and CCR5 in allergic asthma

过敏性哮喘是一种慢性气道炎症性疾病，影响着全世界数百万人。趋化因子RANTES与过敏性哮喘和T细胞依赖性感染清除有关。RANTES受体家族包括CCR1、CCR3和CCR5，它们是由7个跨膜螺旋组成的g蛋白偶联受体。g蛋白偶联受体（gpcr）将生理和感觉刺激转化为细胞反应，并介导三分之一的药物的作用。我们最近报道了哮喘成年患者气道中趋化因子RANTES的上调，表明哮喘气道细胞正在进行细胞激活。此外，在最近未发表的AZCRA研究中，我们发现肺功能较差的哮喘患者与哮喘缓解的患者相比，血清Eotaxin水平升高，Eotaxin是具有促炎特性的第二种趋化因子。在不同欧洲儿童队列的外周血单核细胞中，呼吸道中有鼻病毒的哮喘供体儿童释放较低水平的RANTES。与此一致的是，我们证实了有哮喘和无哮喘的学龄前儿童的PBMCs上清液中RANTES的产生受到抑制，这些儿童在体外感染RV，并在接受抗病毒TLR7/8激动剂治疗后诱导RANTES。我们进一步将这些研究翻译到野生型、RANTES和ccr5缺陷小鼠的屋尘螨（HDM）过敏原诱导的哮喘小鼠模型中。在这里，我们通过协调效应GATA-3+CD4+ T细胞向免疫调节性T细胞和炎性嗜酸性粒细胞向常驻嗜酸性粒细胞的转变，展示了RANTES在变应性哮喘模型中意想不到的治疗作用。在这项研究中，我们希望扩大我们的人类数据，并通过对RANTES、CCR3和CCR5缺陷和条件缺陷小鼠的临床前研究来扩展转化研究，以更好地了解RANTES在哮喘中的细胞和受体介导的调节作用，而不是促炎趋化因子Eotaxin。这些研究可能会导致更好的治疗过敏性疾病，如哮喘

Allergic asthma is a chronic inflammatory disease of the airways that affects millions of people world-wide. Chemokine RANTES is implicated in allergic asthma and in T cell-dependent clearance of infection. RANTES receptor family comprises CCR1, CCR3, and CCR5, which are G-protein-coupled receptors consisting of seven transmembrane helices. G-protein-coupled receptors (GPCRs) transduce physiological and sensory stimuli into cellular responses and mediate the action of one-third of the drugs. We recently reported upregulation of the chemokine RANTES in the airways of asthmatic adult patients indicating ongoing cell activation of airway cells in asthma. Moreover, in recent unpublished AZCRA study, we found that asthmatic patients with worse lung function had increased serum levels of Eotaxin, a second chemokine with pro-inflammatory properties, as compared with those with resolved asthma. In the peripheral blood mononuclear cells in different European cohorts of children, asthmatic donor children with rhinovirus in the airways, released lower levels of RANTES. Consistently, we confirmed suppression of RANTES production in PBMCs supernatants from preschool children with and without asthma, infected in vitro with RV and the induction of RANTES after treatment with the antiviral TLR7/8 agonist. We further translated these studies to a murine model of asthma induced by house dust mite (HDM) allergen in wild-type, RANTES and CCR5-deficient mice. Here we show an unpredicted therapeutic role of RANTES in allergic asthma model of disease by orchestrating the transition of effector GATA-3+CD4+ T cells into immune-regulatory-type T cells and inflammatory eosinophils into resident eosinophils. In this study we want to enlarge our human data and extend the translational studies with pre-clinical studies in RANTES, CCR3 and CCR5 deficient and conditional deficient mice to better understand the cellular and the receptor mediated regulatory role of RANTES as opposed to the pro-inflammatory chemokine Eotaxin in asthma. These studies might lead to better treatment of the allergic diseases like asthma