CCR1- and CCR5-mediated inactivation of leukocytes by a nonglycosaminoglycan (non-GAG)-binding variant of n-Nonanoyl-CCL14 (NNY-CCL14)

Journal of Leukocyte Biology

Wolf-Georg Forssmann¹  Aleksandra Heitland¹  Shipra Gupta⁵  Sylvia E. Escher¹  Ulf Forssmann⁴  Jörn Elsner²  Johanna Manns⁵  Rudolf Richter⁵  Sebastian Rieder⁵  Matthias Mack³  Sandra Schulz-Maronde⁵ 

[1] Immunology and Rheumatology and Immunology and Rheumatology and Immunology and Rheumatology andDermatology, Hannover Medical School, Hannover, Germany; Dermatology, Hannover Medical School, Hannover, Germany; Dermatology, Hannover Medical School, Hannover, Germany;;Department of Internal Medicine, University of Regensburg, Regensburg, Germany; and Department of Internal Medicine, University of Regensburg, Regensburg, Germany; and Department of Internal Medicine, University of Regensburg, Regensburg, Germany; and;Center of Pharmacology and Toxicology and Clinics of Immunology and Rheumatology and IPF PharmaCeuticals GmbH, Affiliated Institute of Hannover Medical School, Hannover, Germany Center of Pharmacology and Toxicology and Clinics of Center of Pharmacology and Toxicology and Clinics of Immunology and Rheumatology and IPF PharmaCeuticals GmbH, Affiliated Institute of Hannover Medical School, Hannover, Germany Immunology and Rheumatology and Center of Pharmacology and Toxicology and Clinics of Immunology and Rheumatology and IPF PharmaCeuticals GmbH, Affiliated Institute of Hannover Medical School, Hannover, Germany IPF PharmaCeuticals GmbH, Affiliated Institute of Hannover Medical School, Hannover, Germany Center of Pharmacology and Toxicology and Clinics of Immunology and Rheumatology and IPF PharmaCeuticals GmbH, Affiliated Institute of Hannover Medical School, Hannover, Germany;Center of Pharmacology and Toxicology and Clinics of Immunology and Rheumatology and Center of Pharmacology and Toxicology and Clinics of Center of Pharmacology and Toxicology and Clinics of Immunology and Rheumatology and Immunology and Rheumatology and Center of Pharmacology and Toxicology and Clinics of Immunology and Rheumatology and

关键词: allergy;    chemokine;    leukocytes;    glycosaminoglycan;   

DOI  :  10.1189/jlb.0509366

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Intervention on chemokine receptors to prevent directional leukocyte migration is a potential therapeutic strategy. NNY-CCL14 is a CD26-resistant lead molecule, which exerts its effects on multiple chemokine receptors (CCR1, CCR2, CCR3, and CCR5). The inhibitory effects of NNY-CCL14 in murine models of allergic airway inflammation have been assigned to its interaction with CCR1 and CCR5. In this study, a non-GAG-binding variant of NNY-CCL14 was generated by mutating basic amino acids within the identified GAG-binding 49BBXB52 motif. This CD26-resistant, non-GAG binding variant, NNY-CCL14(G,A), does not promote CCR1-dependent cell arrest on modeled endothelium. Its biological activity tested on human and murine chemokine receptors revealed distinguishing properties to NNY-CCL14. As suggested by EC50 values for intracellular calcium mobilization, NNY-CCL14(G,A) demonstrated a reduced ability to activate hCCR1, but internalization and desensitization of hCCR1 were unperturbed. Surprisingly, its activity on hCCR3 was strongly reduced, and it did not internalize mCCR3. A significantly reduced chemotactic activity of eosinophils and monocytes was observed. All biological effects mediated by NNY-CCL14(G,A) via hCCR5 and mCCR5 showed no difference to NNY-CCL14. In mice treated i.v. with NNY-CCL14(G,A), a sustained in vivo down-modulation of CCR5 was achieved over 3 h. Therefore, NNY-CCL14(G,A) inactivates leukocytes by desensitizing and internalizing multiple chemokine receptors, thus rendering them unresponsive to further stimulation by natural ligands. When administered systemically, NNY-CCL14(G,A) may modulate leukocyte functions prior to their interaction with other endothelium-bound chemokines expressed under pathophysiological conditions, such as allergic inflammation.

【 授权许可】

Unknown