Chemokine receptors on neutrophils: functionality and involvement in chronic lung disease

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Chronic lung diseases such as cystic fibrosis (CF) or chronic obstructive pulmonary disease (COPD) are characterized by an accumulation of neutrophils. Chemokines recruit and activate neutrophils via chemokine receptors (CR). As G-protein-coupled receptors (GPCRs), CR are highly relevant for therapeutic approaches. Therefore, a detailed knowledge on the involvement of specific CR in chronic lung diseases is required. We previously identified the CR CXCR1 on neutrophils as a critical target in chronic lung disease, since we found that CXCR1 mediates key antibacterial neutrophil functions, but is cleaved proteolytically in protease-dominated airway microenvironments. Proteolytic cleavage disabled bacterial killing and induced the release of glycosylated soluble CXCR1 receptor species. We further found that airway neutrophils in chronic lung diseases change their CR expression profile through translocation of intracellular CR. Based on our previous studies we aim to address the following issues in the proposed research group: (1) To investigate specific cellular pathways in neutrophils engaged through CRs, (2) to identify the molecular mechanisms involved in the cleavage and release of CRs, (3) to characterize the functional role of CRs in murine models of chronic lung disease and (4) to evaluate the therapeutic potential of CR modulation in vivo. These studies will provide important information on the mechanisms involved in the pathogenesis of chronic neutrophilic lung diseases, which could lead to new therapeutic approaches.