ABSTRACT
CCL5 is a functional ligand for both receptors, this observation provides a good example how the presence of a single chemokine can elicit complementary leukocyte responses. Further, this might argue against a functional redundancy, since the expression of both receptors could be a prerequisite for recruiting that particular T-cell type. An interesting aspect of chemokine biology is the variety of processes regulated by chemokines, beyond leukocyte migration. It is well established that chemokines with the N-terminal ELR motive such as CXCL1 and CXCL8 have pro-angiogenic activity, whereas CXC-type chemokines lacking this motive generally act angiostatic [30]. An exception of an angiogenic non-ELR chemokine is CXCL12, which attracts hematopoietic progenitor cells and is implicated in the promotion of tumor angiogenesis [31, 32]. Moreover, CXCL12 is essential in embryogenesis, where it regulates the formation of large vessels and parts of the nervous system [33, 34]. The chemokine receptor CXCR4 has long been considered to be the only receptor for CXCL12, a notion that was supported by the observation that CXCR4 knockout mice showed a similar lethal phenotype as mice lacking CXCL12. However, a novel chemokine receptor, CXCR7, has been identified as a high-affinity receptor for CXCL12. Although CXCR7 does not mediate classical chemokine receptor responses such as chemotaxis or calcium mobilization [35], it has been shown to be important for the formation of functional heart valves during embryonic development in mice [36]. Thus, CXCR7 may not be linked to G-proteins in an ordinary manner, but might rather act as silent chemokine receptor, similar to the scavenger receptor Duffy antigen receptor for chemokines (DARC) [37]. Some of the effects of CXCR7 might be caused by its modulation of CXCR4, which is mediated by heterodimerization of the two receptors [36, 38]. 1.2.2.2 Transportation and clearance of chemokines in
tissues Recent studies have highlighted an importance for the presentation of chemokines during inflammation, e.g., through the manipulation of enzymes involved in the synthesis of GAGs. Endothelium-specific gene deletion of N-deacetylase−N-sulfotransferase-1 (ndst-1), an enzyme essential for the sulfation of heparan sulfate, in mice reduced inflammation in various models [39]. Interestingly, the ability of exogenously administered CXCL1 and CXCL2 to recruit leukocytes into subcutaneous air pouches was also impaired in these mice.
