Investigating the orchestration of the inflammatory response: a role for chemokine receptors CCR1, CCR2, CCR3 and CCR5

QR180 Immunology

Bartolini, Robin ; Wellcome Trust (WELLCOTR) ; Graham, Gerard

University:University of Glasgow

Department:Institute of Infection Immunity and Inflammation

关键词: chemokines, chemokine receptors, CCR1, CCR2, CCR3, CCR5, immune system, leukocytes, migration, chemotaxis, inflammation.;   

Others  :  http://theses.gla.ac.uk/76731/1/2019BartoliniPhD.pdf

来源: University of Glasgow

【 摘 要 】

Despite over 20 years of pharmaceutical targeted research, no antagonist of inflammatory chemokine receptors (iCCR) has been licensed for use in treating inflammatory diseases. Marked promiscuity of ligand binding, simultaneous expression of multiple chemokine receptors in individual leukocytes and the inability to generate compound receptor knock out mice make it almost impossible to discern the function of a specific iCCR (especially for inflammatory CC chemokine receptors CCR1, CCR2, CCR3 and CCR5).To address this complexity, two novel mouse models have been recently developed at the Chemokine Research Group: a full iCCR-/- strain in which the whole chromosomal CC-iCCR cluster has been deleted, (resulting in a compound CCR1, CCR2, CCR3 and CCR5-/- mouse) and a novel iCCR fluorescent reporter strain, which expresses specific fluorescent proteins under the endogenous iCCR promoters.Experiments on the iCCR-/- have provided a ‘clean slate’ to assess the development of the immune response in the absence of CCR1, CCR2, CCR3 and CCR5, while studies on the iREP strain allowed for direct visualisation of changes in iCCR expression on the surface of several leukocyte subsets.The findings presented in this thesis not only validate our current understanding of the crucial roles of CCR2 and CCR3 in the mobilisation of monocytes and eosinophils from the bone marrow to the site of inflammation, but also provide clues on the role of CCR1 in monocyte trans-endothelial migration and describe a novel role for iCCRs in the proliferation and differentiation of dendritic cells and macrophages in vitro.More studies on these new iCCR mouse models will provide clarity on our current understanding of the orchestration of the CC-chemokine driven inflammatory responses, and the results will not only increase our understanding of basic chemokine biology, but could also inform future pharmacological intervention on the chemokine system.