title: A strategy to discover decoy chemokine ligands with an anti-inflammatory activity.
abstract: Excessive signaling by chemokines has been associated with chronic inflammation or cancer, thus attracting substantial attention as promising therapeutic targets. Inspired by chemokine-clearing molecules shaped by pathogens to escape the immune system, we designed a generic screening assay to discover chemokine neutralizing molecules (neutraligands) and unambiguously distinguish them from molecules that block the receptor (receptor antagonists). This assay, called TRIC-r, combines time-resolved intracellular calcium recordings with pre-incubation of bioactive compounds either with the chemokine or the receptor-expressing cells. We describe here the identification of high affinity neutraligands of CCL17 and CCL22, two chemokines involved in the Th2-type of lung inflammation. The decoy molecules inhibit in vitro CCL17- or CCL22-induced intracellular calcium responses, CCR4 endocytosis and human T cell migration. In vivo, they inhibit inflammation in a murine model of asthma, in particular the recruitment of eosinophils, dendritic cells and CD4(+)T cells. Altogether, we developed a successful strategy to discover as new class of pharmacological tools to potently control cell chemotaxis in vitro and in vivo.
authors.affiliation: Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS/Université de Strasbourg, and Labex Medalis, ESBS, 300 Boulevard Sébastien Brant, 67412 Illkirch, France.
authors.forename: Dayana
authors.initials: D
authors.lastname: Abboud
authors.affiliation: Laboratoire d'Innovation Thérapeutique, UMR 7200 CNRS/Université de Strasbourg, and Labex Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
authors.forename: François
authors.initials: F
authors.lastname: Daubeuf
authors.affiliation: GreenPharma, 3 allée du Titane, 45100 Orléans, France.
authors.forename: Quoc Tuan
authors.initials: QT
authors.lastname: Do
authors.affiliation: Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS/Université de Strasbourg, and Labex Medalis, ESBS, 300 Boulevard Sébastien Brant, 67412 Illkirch, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Utard
authors.affiliation: PCBIS Plate-forme de Chimie Biologique Intégrative de Strasbourg, UMS 3286 CNRS/Université de Strasbourg, and Labex Medalis, ESBS, 300 Boulevard Sébastien Brant, 67412 Illkirch, France.
authors.forename: Pascal
authors.initials: P
authors.lastname: Villa
authors.affiliation: Laboratoire d'Innovation Thérapeutique, UMR 7200 CNRS/Université de Strasbourg, and Labex Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Haiech
authors.affiliation: Laboratoire d'Innovation Thérapeutique, UMR 7200 CNRS/Université de Strasbourg, and Labex Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnet
authors.affiliation: Laboratoire d'Innovation Thérapeutique, UMR 7200 CNRS/Université de Strasbourg, and Labex Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
authors.forename: Marcel
authors.initials: M
authors.lastname: Hibert
authors.affiliation: GreenPharma, 3 allée du Titane, 45100 Orléans, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Bernard
authors.affiliation: Biotechnologie et Signalisation Cellulaire, UMR 7242 CNRS/Université de Strasbourg, and Labex Medalis, ESBS, 300 Boulevard Sébastien Brant, 67412 Illkirch, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Galzi
authors.affiliation: Laboratoire d'Innovation Thérapeutique, UMR 7200 CNRS/Université de Strasbourg, and Labex Medalis, Faculté de Pharmacie, 74 route du Rhin, 67401 Illkirch, France.
authors.forename: Nelly
authors.initials: N
authors.lastname: Frossard
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement; D054414:Chemokine CCL17 / Q000378:metabolism*; D054422:Chemokine CCL22 / Q000378:metabolism*; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004804:Eosinophils / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D054398:Receptors, CCR4 / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology
chemical_list: D000893:Anti-Inflammatory Agents; C106230:CCL17 protein, human; C515482:CCL22 protein, human; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D018925:Chemokines; D054398:Receptors, CCR4