TITLE

A strategy to discover decoy chemokine ligands with an anti-inflammatory activity

AUTHOR(S)
Abboud, Dayana; Daubeuf, François; Quoc Tuan Do; Utard, Valérie; Villa, Pascal; Haiech, Jacques; Bonnet, Dominique; Hibert, Marcel; Bernard, Philippe; Galzi, Jean-Luc; Frossard, Nelly
PUB. DATE
October 2015
SOURCE
Scientific Reports;10/9/2015, p1
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
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.
ACCESSION #
110327896

 

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