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

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Jorgensen_2-17tzj3vyovwve7.pdf
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2018
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Jørgensen, Astrid S.
Adogamhe, Pontian E.
Veldkamp, Christopher T.
Rosenkilde, Mette M.
Hjortø, Gertrud M.
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Journal of leukocyte biology. 2018, 104(2), pp. 401-411. ISSN 0741-5400. eISSN 1938-3673. Available under: doi: 10.1002/JLB.2VMA0118-008R
Zusammenfassung

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.

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570 Biowissenschaften, Biologie
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bias signaling, cAMP, chimera, migration, species bias, tail truncation
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ISO 690JØRGENSEN, Astrid S., Pontian E. ADOGAMHE, Julia M. LAUFER, Daniel F. LEGLER, Christopher T. VELDKAMP, Mette M. ROSENKILDE, Gertrud M. HJORTØ, 2018. CCL19 with CCL21-tail displays enhanced glycosaminoglycan binding with retained chemotactic potency in dendritic cells. In: Journal of leukocyte biology. 2018, 104(2), pp. 401-411. ISSN 0741-5400. eISSN 1938-3673. Available under: doi: 10.1002/JLB.2VMA0118-008R
BibTex
@article{Jrgensen2018-08CCL19-42812,
  year={2018},
  doi={10.1002/JLB.2VMA0118-008R},
  title={CCL19 with CCL21-tail displays enhanced glycosaminoglycan binding with retained chemotactic potency in dendritic cells},
  number={2},
  volume={104},
  issn={0741-5400},
  journal={Journal of leukocyte biology},
  pages={401--411},
  author={Jørgensen, Astrid S. and Adogamhe, Pontian E. and Laufer, Julia M. and Legler, Daniel F. and Veldkamp, Christopher T. and Rosenkilde, Mette M. and Hjortø, Gertrud M.}
}
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    <dcterms:abstract xml:lang="eng">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 (CCL19&lt;sup&gt;CCL21-tail&lt;/sup&gt; ) 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 CCL19&lt;sup&gt;CCL21-tail&lt;/sup&gt; compared to CCL21 is not transferred to CCL21 by replacing its N-terminus with that of CCL19 (CCL21&lt;sup&gt;CCL19-N-term&lt;/sup&gt; ). Measurements of cAMP production in CHO cells uncover that CCL21-tail transfer (CCL19&lt;sup&gt;CCL21-tail&lt;/sup&gt; ) negatively affects CCL19 potency, whereas removal of CCL21-tail (&lt;sup&gt;CCL21tailless&lt;/sup&gt; ) 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 (CCL21&lt;sup&gt;CCL19-N-term&lt;/sup&gt; ). Together these results indicate that ligands containing CCL21 core and C-terminal tail (CCL21 and CCL21&lt;sup&gt;CCL19-N-term&lt;/sup&gt; ) 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.</dcterms:abstract>
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