Chemokine CXCL4 interactions with extracellular matrix proteoglycans mediate wide-spread immune cell recruitment independent of chemokine receptors

Anna Gray, Richard Karlsson, Abigail RE Roberts, Amanda Ridley Mainwaring, Nabina Pun, Bakhtbilland Khan, Craig Lawless, Rafael Luis, Martyna Szpakowska, Andy Chevigné, Catherine E Hughes, Laura Medina-Ruiz, Holly Birchenough, Iashia Mulholland, Catherina Salanga, Edwin A. Yates, Jeremy E. Turnbull, Tracy M. Handel, Gerard J Graham, Thomas JowittIngo Schiessl, Ralf P. Richter, Rebecca L Miller, Douglas Dyer

Research output: Contribution to journalArticlepeer-review

Abstract

Leukocyte recruitment from the vasculature into tissues is a crucial component of the immune system but is also key to inflammatory disease. Chemokines are central to this process but have yet to be therapeutically targeted during inflammation, due to a lack of mechanistic understanding. Specifically, CXCL4 (Platelet Factor 4, PF4) has no established receptor that explains its function. Here we use biophysical, in vitro and in vivo techniques to determine the mechanism underlying CXCL4 mediated leukocyte recruitment. We demonstrate that CXCL4 binds to glycosaminoglycan (GAG) sugars on proteoglycans within the endothelial extracellular matrix resulting in increased adhesion of leukocytes to the vasculature, increased vascular permeability and non-specific recruitment of a range of leukocytes. Furthermore, GAG sulphation confers selectivity onto chemokine localisation. These findings represent a new understanding of chemokine biology, providing novel mechanisms for future therapeutic targeting.
Original languageEnglish
Article number111930
JournalCell Reports
Volume42
Issue number1
Early online date5 Jan 2023
DOIs
Publication statusPublished - 31 Jan 2023

Keywords

  • CXCL4
  • PF4
  • Chemokine
  • Proteoglycan
  • Glycosaminoglycan
  • Extracellular Matrix
  • Leukocyte
  • Recruitment
  • Trafficking

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

Fingerprint

Dive into the research topics of 'Chemokine CXCL4 interactions with extracellular matrix proteoglycans mediate wide-spread immune cell recruitment independent of chemokine receptors'. Together they form a unique fingerprint.

Cite this