The P2 receptor antagonist PPADS abrogates LPS-induced neutrophil migration in the murine air pouch via inhibition of MIP-2 and KC production.
In this work, we show that P2 nucleotide receptors control lipopolysaccharide (LPS)-induced neutrophil migration in the mouse air pouch model. Neutrophil infiltration in LPS-treated air pouches was reduced by the intravenous (iv) administration of the non-selective P2 receptor antagonist PPADS but not by suramin and RB-2. In addition, the iv administration of a P2 receptor ligand, UTP, enhanced LPS-induced neutrophil migration. In contrast, the iv injection of UDP had no effect on neutrophil migration. These data suggest that LPS-induced neutrophil migration in the air pouch could involve P2Y(4) receptor which is antagonized by PPADS, activated by UTP, but not UDP, and insensitive to suramin. The inhibition of neutrophil migration by PPADS correlated with a diminished secretion of chemokines macrophage inflammatory protein-2 (MIP-2) and keratinocyte-derived chemokine (KC) in the air pouch exudates. As determined in vitro, PPADS did not affect MIP-2 and KC release from air pouch resident cells nor from accumulated neutrophils. MIP-2 and KC production in the LPS-treated air pouches correlated with an early neutrophil migration (1h after LPS injection), and both of these effects were significantly reduced in mice administered with PPADS. Altogether, these data suggest that P2Y(4) receptor expressed in circulating leukocytes and/or endothelium controls LPS-induced acute neutrophil recruitment in mouse air pouch.
Kukulski
Filip
F
Centre de Recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Québec, Université Laval, 2705 Boulevard Laurier, Local T1-49, Québec, QC G1V 4G2, Canada.
Ben Yebdri
Fethia
F
Bahrami
Fariborz
F
Lévesque
Sébastien A
SA
Martín-Satué
Mireia
M
Sévigny
Jean
J
D000818:Animals; D001081:Apyrase / Q000494:pharmacology; D002465:Cell Movement / Q000187:drug effects*; D054426:Chemokine CXCL2 / Q000096:biosynthesis*; D018925:Chemokines / Q000096:biosynthesis*; D004195:Disease Models, Animal; D005122:Exudates and Transudates / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology*; D017737:Macrophages, Peritoneal / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D051379:Mice; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D058919:Purinergic P2 Receptor Antagonists; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D013583:Synovial Membrane / Q000187:drug effects / Q000473:pathology*; D051193:Toll-Like Receptors / Q000819:agonists; D014544:Uridine Triphosphate / Q000494:pharmacology
D054426:Chemokine CXCL2; D018925:Chemokines; D008070:Lipopolysaccharides; D058919:Purinergic P2 Receptor Antagonists; D051193:Toll-Like Receptors; C074302:keratinocyte-derived chemokines; C077792:pyridoxal phosphate-6-azophenyl-2',4'-disulfonic acid; D011732:Pyridoxal Phosphate; D001081:Apyrase; D014544:Uridine Triphosphate