An investigation of the roles for leukocyte and lymphatic endothelial cell D6 in the orchestration of the in vivo inflammatory response. (360G-Wellcome-081194_Z_06_Z)

Much is known about initiation and maintenance of inflammation but less about the resolution of this response. Prominent amongst inflammatory regulators are chemokines. We have identified an atypical chemokine receptor which we have called D6. D6 binds all CC-chemokines involved in regulating inflammatory responses. In vitro studies have shown that D6 is a scavenging receptor for CC-chemokines and in vivo studies have revealed a role for D6 in the removal of inflammatory CC-chemokines from infla med sites. TPA application to skin leads to the development of a psoriasis-like pathology in D6-null mice. D6 therefore is involved in the resolution of inflammation. Despite evidence for the important in vivo roles for D6 we have a limited understanding of the cellular basis for D6 function. We have reported D6 expression on lymphatic endothelial cells (LECs) in tissues. However we have recently detailed expression of D6 on leukocytes in inflamed sites. This indicates that leukocyte and LEC-exp ressed D6 may contribute in distinct ways to the resolution of inflammatory responses and indeed to the regulation of immune responses. We propose to investigate the relative roles played by leukocyte and LEC-D6 in the regulation of inflammatory responses and the movement of leukocytes to lymph nodes.