Identification Of New Molecules Involved In Dendritic Cell Localization

Bonecchi, Raffaella (2007). Identification Of New Molecules Involved In Dendritic Cell Localization. PhD thesis The Open University.



The present study was designed to investigate the expression and function of an orphan seven transmembrane receptor named CCRL2 (CC chemokine receptor like 2), a putative chemokine receptor. In human tissues CCRL2 was expressed mainly by lung, lymphoid tissues and fetal spleen. Among leukocytes CCRL2 was expressed by monocytes, neutrophils and dendritic cells (DC). Because chemokines play a fundamental role in DC trafficking, modulation of CCLR2 expression in this cell type was further investigated. Maturative stimuli like LPS and CD40L strongly up regulated CCRL2 mRNA and protein in DC. Culture of DC in the presence of inhibitors of maturation and function such as VitD3 and Dex had no effect on LPS-induced CCRL2 up regulation. On the contrary PGE2, that does not affect DC maturation, completely abolished LPS induction of CCRL2 expression. The effect of LPS and CD40L on CCRL2 expression was rapid (1.5h) and transient (maximal at 4h) and declined by 24h, conversely the upregulation of CCR7 that was slower and reached a plateau at 24h of stimulation.

Since CCRL2 gene is located in the main chemokine receptor cluster in the 3p21 chromosome, it is likely to be a conventional inflammatory chemokine receptor. In order to identify ligands CCRL2 transfectants were used in chemotaxis and calcium flux assays with a broad panel of inflammatory CC and CXC chemokines but no ligand was identified. The alterations in the DRYLAR/IV motif in the second intracellular loop suggest that CCRL2 may be a candidate for the family of chemokine decoy receptors like the receptor D6. This second hypothesis was evaluated performing chemokine scavenging assays. None of the chemokine tested was scavenged by CCRL2. However in parallel experiments two new ligands for D6, the CCR4 agonists CCL17 and CCL22 were identified. In summary these data suggest that CCRL2 might be involved in DC trafficking, through the regulation of the DC emigration from tissues following stimulation. None of the chemokine tested was able to bind or activate CCRL2. Furthermore CCRL2 appears not to act as a chemokine scavenger receptor and its biological role is still elusive.

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