The chemokine receptor D6 appears to be involved in clearing -chemokines from inflamed skin and therefore in resolving inflammation.
Although much is known about the initiation of pro-inflammatory responses, relatively little is known about how these responses are resolved. In a recent report in Nature Immunology, Thomas Jamieson et al. show that the chemokine receptor D6 is involved in clearing -chemokines from inflamed skin and therefore in resolving inflammation.
D6 is a seven-membrane-spanning receptor that binds pro-inflammatory members of the -chemokine family, such as CC-chemokine ligand 2(CCL2; also known as MCP1) and CCL3 (also known as MIP1), but it does not bind constitutively expressed -chemokines, such as CCL19 and CCL21. However, unlike other chemokine receptors, D6 does not seem to signal after ligand binding but, instead, internalizes its ligands and targets them for degradation, indicating that D6 might function as a decoy receptor. So, to test the in vivo functions of D6, the authors generated D6-deficient mice and analysed their responses in models of cutaneous inflammation. At 8 and 18 hours after the induction of inflammation in the skin by the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA), the concentrations of CCL2 and CCL3 were similar in the skin of both D6-deficient and wild-type mice. However, by 24 hours, the concentrations of these chemokines were significantly higher in the D6-deficient mice, which is consistent with a role for D6 in the post-inflammatory clearance of -chemokines from the skin. By contrast, levels of the non-D6-binding chemokine CXC-chemokine ligand 2 (CXCL2; also known as MIP2) did not differ between wild-type and D6-deficient mice at any time point.
The authors next asked whether the increased concentrations of residual pro-inflammatory -chemokines had pathological consequences. Indeed, although inflammation in wild-type mice induced by 3 applications of TPA resolved after 4 days, D6-deficient mice developed skin pathology that was characterized by epidermal hyperproliferation and inflammatory-cell infiltration — similar to the pathology of human psoriasis. They showed that this process was dependent on tumour-necrosis factor (TNF), as TNF-specific antibodies completely abrogated the psoriasiform pathology. Further analysis of the inflammatory infiltrate indicated that T cells and mast cells accumulated at high levels in the inflamed skin of D6-deficient mice but not in that of wild-type mice. Infiltration of T cells into the epidermis was partially responsible for the subsequent accumulation of dermal mast cells, which contribute to development of the pathology through their release of granule products.
So, D6 functions in vivo as a decoy receptor, clearing away residual -chemokines in inflamed skin, thereby helping to avoid aberrant recruitment of inflammatory cells and subsequent pathology.
Lucy Bird
References
Jamieson, T. et al. The chemokine receptor D6 limits the inflammatory response in vivo . Nature Immunol.6, 403–411 (2005) | Article |
-chemokines from inflamed skin and therefore in resolving inflammation.
), but it does not bind constitutively expressed 