Chemokine CXCL4 interactions with extracellular matrix proteoglycans mediate widespread immune cell recruitment independent of chemokine receptors

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

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

18 Citations (Scopus)

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 sulfation confers selectivity onto chemokine localization. These findings present mechanistic insights into chemokine biology and provide future therapeutic targets.

Original languageEnglish
Article number111930
JournalCell Reports
Volume42
Issue number1
Early online date5 Jan 2023
DOIs
Publication statusPublished - 31 Jan 2023

Keywords

  • chemokine
  • CP: Immunology
  • CXCL4
  • extracellular matrix
  • glycosaminoglycan
  • leukocyte
  • PF4
  • proteoglycan
  • recruitment
  • trafficking

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