Journal of Leukocyte Biology BioLegend: Treg, Th17, Stem Cell
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Originally published online as doi:10.1189/jlb.0607429 on December 6, 2007

Published online before print December 6, 2007
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(Journal of Leukocyte Biology. 2008;83:765-773.)
© 2008 by Society for Leukocyte Biology

Intravascular inactivation of CCR5 by n-Nonanoyl-CC chemokine ligand 14 and inhibition of allergic airway inflammation

Shipra Gupta*, Barbara Fuchs{dagger}, Sandra Schulz-Maronde*, Aleksandra Heitland*, Sylvia E. Escher*, Matthias Mack{ddagger}, Hanns-Christian Tillmann§, Armin Braun{dagger}, Wolf-Georg Forssmann*, Jörn Elsner|| and Ulf Forssmann*,¶,1

* Center of Pharmacology and Toxicology, Hannover Medical School, Hannover, Germany;
{dagger} Fraunhofer Institute of Toxicology and Experimental Medicine, Hannover, Germany;
{ddagger} Department of Internal Medicine, University of Regensburg, Regensburg, Germany;
§ VIRO Pharmaceuticals GmbH & Co. KG, Hannover, Germany;
|| Department of Dermatology and Allergology, Fachklinik Bad Bentheim, Germany; and
IPF PharmaCeuticals GmbH, Affiliated Institute of Hannover Medical School, Hannover, Germany

1Correspondence: Center of Pharmacology and Toxicology, Hannover Medical School, Feodor-Lynen-Strasse 31, 30625 Hannover, Germany. E-mail: u.forssmann{at}gmx.de

ABSTRACT

Modulation of leukocyte recruitment through intervention with chemokine receptors is an attractive, therapeutic strategy. Recently, we have shown that n-Nonanoyl (NNY)-CCL14 internalizes and desensitizes human (h)CCR3, resulting in the inactivation of eosinophils. In this study, we investigated the interaction of NNY-CCL14 with CCR1 and CCR5 and the relevance of these NNY-CCL14 receptors on its in vivo effects in allergic airway inflammation. NNY-CCL14 has inactivating properties on CCR1+ and CCR5+ cell lines and primary leukocytes. It desensitizes hCCR1- and hCCR5-mediated calcium release and internalizes these receptors from the cellular surface. Treatment of OVA-sensitized BALB/c mice with NNY-CCL14 resulted in reduced pulmonary inflammation. Above all, it is demonstrated that systemic treatment with NNY-CCL14 down-modulates CCR5 from the surface of lymphocytes in vivo. Although NNY-CCL14 acts on murine lymphocytes and internalizes CCR5, it does not internalize CCR3 on mouse eosinophils, showing species selectivity regarding this particular receptor. Therefore, the inhibitory effects of NNY-CCL14 in murine models of allergic airway inflammation can be assigned to its interaction with CCR5. The presented results substantiate the relevance of CCR5 as a target for allergic airway inflammation.

Key Words: allergy • chemokines • human • lymphocytes • mouse






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