Chemokines and galectins form heterodimers to modulate inflammation

Veit Eckardt, Michelle C. Miller, Xavier Blanchet, Rundan Duan, Julian Leberzammer, Johan Duchene, Oliver Soehnlein, Remco T. A. Megens, Anna-Kristin Ludwig, Aurelio Dregni, Alexander Faussner, Kanin Wichapong, Hans Ippel, Ingrid Dijkgraaf, Herbert Kaltner, Yvonne Doering, Kiril Bidzhekov, Tilman M. Hackeng, Christian Weber, Hans-Joachim GabiusPhilipp von Hundelshausen*, Kevin H. Mayo

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

34 Citations (Web of Science)

Abstract

Chemokines and galectins are simultaneously upregulated and mediate leukocyte recruitment during inflammation. Until now, these effector molecules have been considered to function independently. Here, we tested the hypothesis that they form molecular hybrids. By systematically screening chemokines for their ability to bind galectin-1 and galectin-3, we identified several interacting pairs, such as CXCL12 and galectin-3. Based on NMR and MD studies of the CXCL12/galectin-3 heterodimer, we identified contact sites between CXCL12 beta-strand 1 and Gal-3 F-face residues. Mutagenesis of galectin-3 residues involved in heterodimer formation resulted in reduced binding to CXCL12, enabling testing of functional activity comparatively. Galectin-3, but not its mutants, inhibited CXCL12-induced chemotaxis of leukocytes and their recruitment into the mouse peritoneum. Moreover, galectin-3 attenuated CXCL12-stimulated signaling via its receptor CXCR4 in a ternary complex with the chemokine and receptor, consistent with our structural model. This first report of heterodimerization between chemokines and galectins reveals a new type of interaction between inflammatory mediators that can underlie a novel immunoregulatory mechanism in inflammation. Thus, further exploration of the chemokine/galectin interactome is warranted.

Original languageEnglish
Article number47852
Number of pages17
JournalEmbo Reports
Volume21
Issue number4
DOIs
Publication statusPublished - 3 Apr 2020

Keywords

  • chemotaxis
  • CXCL12
  • G protein-coupled receptor
  • galectin-3
  • lectin
  • T-CELLS
  • BINDING
  • ATHEROSCLEROSIS
  • NEUTROPHILS
  • DIMERIZATION
  • TRAFFICKING
  • RECEPTORS
  • MOLECULE
  • PATTERNS

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