Probing atypical chemokine biology

CCL18 has been reported to be present at high constitutive levels in the circulation and is further elevated in inflammatory disease. Functional cellular responses mediated by CCL18 have been described, however its signalling chemokine receptor remains elusive. In this manuscript we show that CCL18 recruits certain leukocyte subsets, albeit with weak efficacy. We investigated whether CCL18 is modified under inflammatory conditions to produce a more potent chemoattractant, but only minor truncations were observed, indicating that the mature form of CCL18 seems to be the biological relevant form. Our studies indicate a potential anti-inflammatory role of CCL18 based on the selective displacement of GAG-bound chemokines as well as the inhibition of cellular recruitment mediated by a variety of chemokine receptors. The 44KRGR47 cluster in the 40s loop is implicated in heparin binding and in the interaction with CCR3, 4 and 5. In regard to the lack of potent immunomodulatory properties the complex formation of CCL18 with the tick chemokine binding proteins Evasin-1 and -4 was confirmed. In a smaller study the binding properties of CCL2 in rat brain were investigated. Binding studies revealed strong evidence for D6 receptor expression, primarily in the rat brain cortex. This might indicate a role of D6 in behaviour, for which the cortex was shown to play a pivotal role