A Strategy to Discover Decoy Chemokine Ligands with an Anti-inflammatory Activity

Overview

Journal Sci Rep

Specialty Science

Date 2015 Oct 8

PMID 26442456

Citations 11

Authors

Dayana Abboud

Francois Daubeuf

Quoc Tuan Do

Valerie Utard

Pascal Villa

Jacques Haiech

Dominique Bonnet

Marcel Hibert

Philippe Bernard

Jean-Luc Galzi

Nelly Frossard

Affiliations

Soon will be listed here.

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.

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