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

RANTES 及其受体 CCR3 和 CCR5 在过敏性哮喘中的功能作用

• 批准号: 517590146
• 负责人: Professorin Dr. Susetta Finotto, Ph.D.
• 金额: --
• 依托单位: Abteilung Molekulare Pneumologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/517590146?language=en
• 关键词: Functional; role; RANTES; its; receptors

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 Moreover, in recent unpublished AZCRA study, we found that asthmatic patients with worse lung function had increased serum levels of Eotaxin, a second chemokine with pro-inflammatory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

过敏性哮喘是一种慢性气道炎症性疾病，影响全球数百万人。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CCR 1、CCR 3和CCR 5，它们是由七个跨膜螺旋组成的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，并介导三分之一药物的作用。我们最近报道了趋化因子RANTES在成人哮喘患者气道中的上调，表明哮喘患者气道细胞的持续细胞活化。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。在不同的欧洲儿童队列的外周血单核细胞中，气道中有鼻病毒的哮喘供体儿童释放较低水平的RANTES。因此，我们证实了在体外RV感染的学龄前哮喘儿童和非哮喘儿童的PBMC上清液中RANTES的产生受到抑制，并且在用抗病毒TLR 7/8激动剂治疗后诱导RANTES。我们进一步将这些研究转化为由屋尘螨（HDM）变应原在野生型、RANTES和CCR 5缺陷小鼠中诱导的哮喘小鼠模型。在此，我们通过协调效应加塔-3 + CD 4 + T细胞向免疫调节型T细胞和炎性嗜酸性粒细胞向常驻嗜酸性粒细胞的转变，显示了RANTES在过敏性哮喘疾病模型中不可预测的治疗作用。在这项研究中，我们希望扩大我们的人类数据，并扩展RANTES，CCR 3和CCR 5缺陷和条件缺陷小鼠的临床前研究的转化研究，以更好地了解RANTES的细胞和受体介导的调节作用，而不是促炎趋化因子Eotaxin在哮喘中。这些研究可能会导致更好的治疗过敏性疾病，如哮喘