Intravascular inactivation of CCR5 by n-Nonanoyl-CC chemokine ligand 14 and inhibition of allergic airway inflammation.
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.
Gupta
Shipra
S
Center of Pharmacology and Toxicology, Hannover Medical School, Feodor-Lynen-Strasse 31, 30625 Hannover, Germany.
Fuchs
Barbara
B
Schulz-Maronde
Sandra
S
Heitland
Aleksandra
A
Escher
Sylvia E
SE
Mack
Matthias
M
Tillmann
Hanns-Christian
HC
Braun
Armin
A
Forssmann
Wolf-Georg
WG
Elsner
Jörn
J
Forssmann
Ulf
U
D000818:Animals; D065100:CCR5 Receptor Antagonists; D054413:Chemokine CCL11 / Q000502:physiology; D054405:Chemokine CCL3 / Q000502:physiology; D019742:Chemokines, CC / Q000494:pharmacology*; D006801:Humans; D006967:Hypersensitivity / Q000517:prevention & control*; D007249:Inflammation / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D010047:Ovalbumin / Q000276:immunology; D054389:Receptors, CCR1 / Q000502:physiology; D019713:Receptors, CCR5 / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
C515300:CCR1 protein, human; D065100:CCR5 Receptor Antagonists; D054413:Chemokine CCL11; D054405:Chemokine CCL3; D019742:Chemokines, CC; D054389:Receptors, CCR1; D019713:Receptors, CCR5; D010047:Ovalbumin