Enhanced adhesive capacities of the naturally occurring Ile249-Met280 variant of the chemokine receptor CX3CR1.
It was recently shown that individuals carrying the naturally occurring mutant CX3CR1-Ile(249)-Met(280) (hereafter called CX3CR1-IM) have a lower risk of cardiovascular disease than individuals homozygous for the wild-type CX3CR1-Val(249)-Thr(280) (CX3CR1-VT). We report here that peripheral blood mononuclear cells (PBMC) from individuals with the CX3CR1-IM haplotype adhered more potently to membrane-bound CX3CL1 than did PBMC from homozygous CX3CR1-VT donors. Similar excess adhesion was observed with CX3CR1-IM-transfected human embryonic kidney (HEK) cell lines tested with two different methods: the parallel plate laminar flow chamber and the dual pipette aspiration technique. Suppression of the extra adhesion in the presence of pertussis toxin indicates that G-protein mediated the underlying transduction pathway, in contrast to the G-protein-independent adhesion previously described for CX3CR1-VT. Surprisingly, HEK and PBMC that expressed CX3CR1-IM and -VT were indistinguishable when tested with the soluble form of CX3CL1 for chemotaxis, calcium release, and binding capacity. In conclusion, only the membrane-anchored form of CX3CL1 functionally discriminated between these two allelic isoforms of CX3CR1. These results suggest that each form of this ligand may lead to a different signaling pathway. The extra adhesion of CX3CR1-IM may be related to immune defenses and to atherogenesis, both of which depend substantially on adhesive intercellular events.
Laboratoire d'Immunologie Cellulaire, INSERM U543, Faculté de Médecine Pitié-Salpêtrière, 91 Boulevard de l'Hôpital, 75013 Paris, France.
Mehdi
M
Daoudi
Elise
E
Lavergne
Alexandre
A
Garin
Nadine
N
Tarantino
Patrice
P
Debré
Frédéric
F
Pincet
Christophe
C
Combadière
Philippe
P
Deterre
D015153:Blotting, Western; D000073883:CX3C Chemokine Receptor 1; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D002633:Chemotaxis; D005434:Flow Cytometry; D006720:Homozygote; D006801:Humans; D007532:Isoleucine / Q000737:chemistry*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry* / Q000235:genetics*; D008715:Methionine / Q000737:chemistry*; D009154:Mutation; D037342:Pertussis Toxin / Q000494:pharmacology; D011485:Protein Binding; D019707:Receptors, Chemokine / Q000737:chemistry* / Q000235:genetics*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection
D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; D008565:Membrane Proteins; D019707:Receptors, Chemokine; D007532:Isoleucine; D008715:Methionine; D037342:Pertussis Toxin; D002118:Calcium