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Inflammatory chemokines and their receptors are central to the development of inflammatory/immune pathologies. The apparent complexity of this system, coupled with lack of appropriate in vivo models, has limited our understanding of how chemokines orchestrate inflammatory responses and has hampered attempts at targeting this system in inflammatory disease. Novel approaches are therefore needed to provide crucial biological, and therapeutic, insights into the chemokine-chemokine receptor family. Here, we report the generation of transgenic multi-chemokine receptor reporter mice in which spectrally distinct fluorescent reporters mark expression of CCRs 1, 2, 3, and 5, key receptors for myeloid cell recruitment in inflammation. Analysis of these animals has allowed us to define, for the first time, individual and combinatorial receptor expression patterns on myeloid cells in resting and inflamed conditions. Our results demonstrate that chemokine receptor expression is highly specific, and more selective than previously anticipated.

Additional file 1: Supplementary Figures 1, 2 and 3.

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.