Identification and Molecular Characterization of Fractalkine Receptor CX3CR1, which Mediates Both Leukocyte Migration and Adhesion

Abstract

Leukocyte trafficking at the endothelium requires both cellular adhesion molecules and chemotactic factors. Fractalkine, a novel transmembrane molecule with a CX3C-motif chemokine domain atop a mucin stalk, induces both adhesion and migration of leukocytes. Here we identify a seven-transmembrane high-affinity receptor for fractalkine and show that it mediates both the adhesive and migratory functions of fractalkine. The receptor, now termed CX3CR1, requires pertussis toxin-sensitive G protein signaling to induce migration but not to support adhesion, which also occurs without other adhesion molecules but requires the architecture of a chemokine domain atop the mucin stalk. Natural killer cells predominantly express CX3CR1 and respond to fractalkine in both migration and adhesion. Thus, fractalkine and CX3CR1 represent new types of leukocyte trafficking regulators, performing both adhesive and chemotactic functions.

Site‐directed mutagenesis of the chemokine receptor CXCR6 suggests a novel paradigm for interactions with the ligand CXCL16

“…This is also true for CX3CL1-mediated adhesion [36,37]. Interestingly, an N-terminally extended form of CXCL16 was still able to induce significant CXCR6 activation, suggesting that a model in which the chemokine N terminus interacts with an intrahelical binding pocket containing E274 of CXCR6 is unlikely to explain activation of this chemokine receptor.…”

Expression of fractalkine and its receptor, CX3CR1, in atopic dermatitis: Possible contribution to skin inflammation

“…The membrane-bound FKN is able to mediate firm adhesion of CX 3 CR1-expressing leukocytes without requiring selectin-mediated rolling or activation of integrins 18,19 . Furthermore, FKN is released from the cell surface by proteolytic cleavage as soluble FKN (sFKN) that has potent chemoattractant activity for CX 3 CR1 + leukocytes and activates them 12,17,20 …”

Fractalkine mediates T cell–dependent proliferation of synovial fibroblasts in rheumatoid arthritis

“…FKN and its receptor CX 3 CR1 were abundantly expressed on day 18, a time of intense inflammation in the rat joint. Soluble FKN is produced by proteolytic cleavage of membrane-bound FKN, and it has been suspected that its major functions are chemotactic and proadhesive (20). Accordingly, inhibition of FKN can ameliorate murine collageninduced arthritis (31).…”

“…Its chemokine domain is displayed on a long negatively charged mucin-rich stalk extending from the cell surface. When cleaved from the cell membrane, FKN yields a soluble form (sFKN) (19,20). In RA synovium, the major source of FKN is FLS (18), but synovial macrophages and endothelial cells may also produce this chemokine.…”