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Article Dans Une Revue Scientific Reports Année : 2015

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

Résumé

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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Dates et versions

hal-02193983 , version 1 (25-07-2019)

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Dayana Abboud, Francois Daubeuf, Quoc Tuan Do, Valérie Utard, Pascal Villa, et al.. A strategy to discover decoy chemokine ligands with an anti-inflammatory activity. Scientific Reports, 2015, 5, pp.14746. ⟨10.1038/srep14746⟩. ⟨hal-02193983⟩
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