S'abonner

Identification of CCL17 neutraligands targeting atopic diseases - 04/04/15

Doi : 10.1016/j.rmr.2015.02.030 
D. Abboud 1, 4, , F. Daubeuf 2, 4, V. Utard 1, 4, D. Bonnet 2, 4, M. Hibert 2, 4, P. Bernard 3, J.L. Galzi 1, 4, N. Frossard 2, 4
1 Biotechnologie et signalisation cellulaire, UMR 7242 CNRS, Université de Strasbourg, ESBS, Illkirch, France 
2 Laboratoire d’Innovation Thérapeutique, UMR 7200 CNRS, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France 
3 GreenPharma, Orléans, France 
4 LabEx Medalis, Strasbourg, France 

Corresponding author.

Bienvenue sur EM-consulte, la référence des professionnels de santé.
Article gratuit.

Connectez-vous pour en bénéficier!

Résumé

Introduction

Chemokines constitute a family of small cytokines that attract and activate leukocytes during the inflammatory response. Among them, the β-chemokine CCL17 formerly known as thymus- and activation regulated chemokine (TARC), is involved in the development of atopic disorders such as asthma and atopic dermatitis. This chemokine exerts its biological effects by binding to and activating the CCR4 cell-surface receptor that belongs to the Gi-protein-coupled receptor family. Enhanced expression of CCL17 as well as elevated recruitment of CCR4+ Th2 cells have been observed in asthma and atopic dermatitis. To date, most therapeutic strategies have focused on disrupting the chemokine/receptor interaction through use of chemokine receptor antagonists. We have discovered a novel class of small chemical molecules called “neutraligands” that bind to the chemokine itself, not to the receptor, and neutralize its biological activity. The concept has already been fully validated with the discovery of “chalcone 4”, a small chemical that binds CXCL12, thereby preventing bronchial inflammation and hyperresponsiveness in animal models of asthma (Hachet-Haas et al., JBC 2008; Galzi et al., Pharmacol Ther 2010; Gasparik et al., ACS Med Chem Lett 2012; Daubeuf et al., JBC 2013).

Our aim was to identify new CCL17 neutraligands, and evaluate their in vivo activity in mouse models of cutaneous and respiratory Th2-driven allergic inflammation.

Methods

We have set up a cell-based high throughput assay to identify new CCL17 neutraligands. HEK293 cells were transfected with the CCL17 receptor, CCR4, together with the G protein Gαqi5 that will increase the intracellular Ca2+ response (FlexStation3) upon activation with CCL17. A library of pure natural substances, as well as a subset of the academic library of Strasbourg (1000 compounds) was screened. The hits were tested in two Th2-driven murine models:

– an 8-day model of allergic hypereosinophilia to ovalbumin;

– a model of allergic dermatitis to MC903 (calcipotriol).

Results

Two hit molecules were selected from the HTS assay, compounds A and B, with CCL17-neutralizing activity: when preincubated with the chemokine, they blocked CCL17-induced Ca2+ responses (2μg/mL; IC50s=5 and 8μM, respectively); by contrast, when preincubated with the cells, i.e. with the CCR4 receptor, the Ca2+ responses were not affected, indicating the compounds were CCL17 neutraligands and not CCR4 receptor antagonists.

We show that compounds A and B (350μmol/kg, I.P.) significantly reduced the number of cells collected in broncho-alveolar lavage fluid, in particular eosinophils (40 and 60% inhibition, respectively) in the model of allergic hypereosinophilia. In addition, compounds A and B (350μmol/kg) administered topically prevented MC903-induced ear redness and thickness, and decreased plasma IgE levels (by 90%).

Conclusion

Our results show successful identification of CCL17 neutraligands that efficiently control Th2 inflammation, and will help understand the role of CCL17 in asthma and atopic dermatitis.

Le texte complet de cet article est disponible en PDF.

Plan


© 2015  Publié par Elsevier Masson SAS.
Ajouter à ma bibliothèque Retirer de ma bibliothèque Imprimer
Export

    Export citations

  • Fichier

  • Contenu

Vol 32 - N° 3

P. 315 - mars 2015 Retour au numéro
Article précédent Article précédent
  • Role of mitochondrial biogenesis in asthmatic airway smooth muscle proliferation: Forever young
  • V. Siao, I. Dupin, O. Ousova, E. Maurat, P.O. Girodet, R. Marthan, P. Berger, T. Trian, M. Fayon
| Article suivant Article suivant
  • Thymic stromal lymphopoietin induces cytokine production by human lung macrophages
  • T. Victoni, C. Abrial, H. Salvator, M. Brollo, S. Grassin Delyle, V. Lagente, E. Naline, P. devillier

Bienvenue sur EM-consulte, la référence des professionnels de santé.

Mon compte


Plateformes Elsevier Masson

Déclaration CNIL

EM-CONSULTE.COM est déclaré à la CNIL, déclaration n° 1286925.

En application de la loi nº78-17 du 6 janvier 1978 relative à l'informatique, aux fichiers et aux libertés, vous disposez des droits d'opposition (art.26 de la loi), d'accès (art.34 à 38 de la loi), et de rectification (art.36 de la loi) des données vous concernant. Ainsi, vous pouvez exiger que soient rectifiées, complétées, clarifiées, mises à jour ou effacées les informations vous concernant qui sont inexactes, incomplètes, équivoques, périmées ou dont la collecte ou l'utilisation ou la conservation est interdite.
Les informations personnelles concernant les visiteurs de notre site, y compris leur identité, sont confidentielles.
Le responsable du site s'engage sur l'honneur à respecter les conditions légales de confidentialité applicables en France et à ne pas divulguer ces informations à des tiers.


Tout le contenu de ce site: Copyright © 2024 Elsevier, ses concédants de licence et ses contributeurs. Tout les droits sont réservés, y compris ceux relatifs à l'exploration de textes et de données, a la formation en IA et aux technologies similaires. Pour tout contenu en libre accès, les conditions de licence Creative Commons s'appliquent.