title: Analysis of the chemokine receptor CCR3 and its role in the pathogenesis of allergic asthma
title: Analyse des Chemokinrezeptors CCR3 und seiner Rolle in der Pathogenese des allergischen Asthmas
Creators: name: Krammer, Susanne
Publisher: name: Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU)
Year: 2025

description: Asthma bronchiale is a chronic disease that affects a large number of people worldwide and results in a high burden of disease. Due to the contact with airborne allergens, patients suffering from allergic asthma experience acute asthma attacks, characterized by shortness of breath, chest tightness and coughing. The progression of the disease leads to chronic lung inflammation and structural remodelling of the airways causing airway obstruction. Since there is no cure for asthma yet, the current therapy aims only at treating the symptoms and reducing the inflammatory response. The underlying immune response is highly complex and involves a variety of immune cells. Chemokines are important mediators in the correct localization of these different immune players that need to be directed to the site of inflammation. They are involved in cell migration, survival and also mediation of effector functions. CCR3 has been described primarily as a driver of eosinophil chemotaxis. However, more recent studies demonstrate its importance for mast cells, macrophages, T cells and dendritic cells. Moreover, CCR3 is expressed on structural cells such as epithelial cells or airway smooth muscle cells, suggesting its great relevance for allergic diseases including asthma bronchiale. The present study aims at analysing the role of the chemokine receptor CCR3 in the pathogenesis of allergic asthma in more detail. In a human cohort of healthy controls and asthmatic patients, the expression of CCR3 and its ligands RANTES and eotaxin was investigated in peripheral blood cells. CCR3 expression was found to be increased in asthmatic patients and associated with worse lung function and higher blood eosinophil numbers. For further analysis, a CCR3-deficient mouse strain was used in a house dust mite-induced allergic asthma model. In the absence of CCR3, mice developed severe airway hyperresponsiveness while showing reduced eosinophilic inflammation and lower IgE levels as compared to wild-type mice. When investigating other inflammatory cells in the airways, mast cells and neutrophils were found increased in CCR3-deficient mice as compared to wild-type littermates. CCR3 KO mice showed a strong TH2 polarisation but were unable to properly release TH2 cytokines due to a reduced calcium influx in the absence of CCR3 activation. Moreover, numbers of MHCI cross-presenting cDC1 and γδ T cells were increased in CCR3 KO mice resulting in induced antigen-cross presentation in vitro. In vivo, CCR3 KO mice presented reduced CD8 T cell numbers in the lung compartment. CCR3-deficient CD8 T cell subsets shifted towards a more pronounced tissue-resident phenotype and had reduced numbers of CD8 effector-memory T cells. The CCR3-deficient CD8 T cell population was characterized by an extended chemokine receptor repertoire, reduced IL-4 signalling and the expression of exhaustion markers. Additionally, their integrin expression was increased while the production of cytotoxic mediators was significantly reduced. In summary, this work provides a better understanding of the involvement of CCR3 in the orchestration of asthmatic lung inflammation and its impact on different immune cell subsets. The presented results suggest a functional impact of CCR3 expression and activation on eosinophils, CD8 T cells, mast cells and dendritic cells which could represent new specific targets for future immunotherapy of asthma bronchiale.