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

• Applicant: Professorin Susetta Finotto, Ph.D.
• Subject Area: Clinical Immunology and Allergology ; Pneumology, Thoracic Surgery
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 517590146

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 Moreover, in recent unpublished AZCRA study, we found that asthmatic patients with worse lung function had increased serum levels of Eotaxin, a second chemokine with pro-inflammatory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

• DFG Programme: Research Grants