CCL19 with CCL21-tail displays enhanced glycosaminoglycan binding with retained chemotactic potency in dendritic cells

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

article

Astrid S. Jørgensen¹  Pontian E. Adogamhe²  Julia M. Laufer³  Daniel F. Legler³  Christopher T. Veldkamp²  Mette M. Rosenkilde¹  Gertrud M. Hjortø¹ 

[1] Department of Biomedical Sciences, Faculty of Health and Medical Sciences, The Panum Institute, University of Copenhagen;Department of Chemistry, University of Wisconsin-Whitewater;Biotechnology Institute Thurgau (BITg), at the University of Konstanz

关键词: bias signaling;    cAMP;    chimera;    migration;    species bias;    tail truncation;   

DOI  :  10.1002/JLB.2VMA0118-008R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

CCL19 is more potent than CCL21 in inducing chemotaxis of human dendritic cells (DC). This difference is attributed to 1) a stronger interaction of the basic C-terminal tail of CCL21 with acidic glycosaminoglycans (GAGs) in the environment and 2) an autoinhibitory function of this C-terminal tail. Moreover, different receptor docking modes and tissue expression patterns of CCL19 and CCL21 contribute to fine-tuned control of CCR7 signaling. Here, we investigate the effect of the tail of CCL21 on chemokine binding to GAGs and on CCR7 activation. We show that transfer of CCL21-tail to CCL19 (CCL19CCL21-tail) markedly increases binding of CCL19 to human dendritic cell surfaces, without impairing CCL19-induced intracellular calcium release or DC chemotaxis, although it causes reduced CCR7 internalization. The more potent chemotaxis induced by CCL19 and CCL19CCL21-tail compared to CCL21 is not transferred to CCL21 by replacing its N-terminus with that of CCL19 (CCL21CCL19-N-term). Measurements of cAMP production in CHO cells uncover that CCL21-tail transfer (CCL19CCL21-tail) negatively affects CCL19 potency, whereas removal of CCL21-tail (CCL21tailless) increases signaling compared to full-length CCL21, indicating that the tail negatively affects signaling via cAMP. Similar to chemokine-driven calcium mobilization and chemotaxis, the potency of CCL21 in cAMP is not improved by transfer of the CCL19 N-terminus to CCL21 (CCL21CCL19-N-term). Together these results indicate that ligands containing CCL21 core and C-terminal tail (CCL21 and CCL21CCL19-N-term) are most restricted in their cAMP signaling; a phenotype attributed to a stronger GAG binding of CCL21 and defined structural differences between CCL19 and CCL21.

【 授权许可】

CC BY