Heparin-bound chemokine CXCL8 monomer and dimer are impaired for CXCR1 and CXCR2 activation: Implications for gradients and neutrophil trafficking

Prem Raj B. Joseph, Kirti V. Sawant, Krishna Rajarathnam

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Chemokine CXCL8 plays a pivotal role in host immune response by recruiting neutrophils to the infection site. CXCL8 exists as monomers and dimers, and mediates recruitment by interacting with glycosaminoglycans (GAGs) and activating CXCR1 and CXCR2 receptors. How CXCL8 monomer and dimer interactions with both receptors and GAGs mediate trafficking is poorly understood. In particular, both haptotactic (mediated by GAGbound chemokine) and chemotactic (mediated by soluble chemokine) gradients have been implicated, and whether it is the free or the GAG-bound CXCL8 monomer and/or dimer that activates the receptor remains unknown. Using solution NMR spectroscopy, we have now characterized the binding of heparin-bound CXCL8 monomer and dimer to CXCR1 and CXCR2 receptor N-domains. Our data provide compelling evidence that heparin-bound monomers and dimers are unable to bind either of the receptors. Cellular assays also indicate that heparin-bound CXCL8 is impaired for receptor activity. Considering dimer binds GAGs with higher affinity, dimers will exist predominantly in the GAG-bound form and the monomer in the free form. We conclude that GAG interactions determine the levels of free CXCL8, and that it is the free, and not GAG-bound, CXCL8 that activates the receptors and mediates recruitment of blood neutrophils to the infected tissue.

Original languageEnglish (US)
Article number170168
JournalOpen Biology
Volume7
Issue number11
DOIs
StatePublished - 2017

Keywords

  • Chemokine
  • GPCR
  • Glycosaminoglycan
  • Gradients
  • NMR
  • Neutrophil

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

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