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

Gray, AL; Karlsson, R; Roberts, ARE; Ridley, AJL; Pun, N; Khan, B; Lawless, C; Luís, R; Szpakowska, M; Chevigné, A; Hughes, CE; Medina-Ruiz, L; Yates, EA; Turnbull, J; Handel, TM; Graham, GJ; Jowitt, TA; Schiessl, I; Richter, RP; Miller, RL; Dyer, DP; Birchenough, HL; Mulholland, IZ; Salanga, CL

doi:10.1016/j.celrep.2022.111930

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

Gray, AL; Karlsson, R; Roberts, ARE; Ridley, AJL; Pun, N; Khan, B; Lawless, C; Luís, R; Szpakowska, M; Chevigné, A; Hughes, CE; Medina-Ruiz, L; Yates, EA; Turnbull, J; Handel, TM; Graham, GJ; Jowitt, TA; Schiessl, I; Richter, RP; Miller, RL; Dyer, DP; Birchenough, HL; Mulholland, IZ; Salanga, CL

Authors

AL Gray

R Karlsson

ARE Roberts

AJL Ridley

N Pun

B Khan

C Lawless

R Luís

M Szpakowska

A Chevigné

CE Hughes

L Medina-Ruiz

EA Yates

Jeremy Turnbull j.e.turnbull@keele.ac.uk

TM Handel

GJ Graham

TA Jowitt

I Schiessl

RP Richter

RL Miller

DP Dyer

HL Birchenough

IZ Mulholland

CL Salanga

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.

Citation

Gray, A., Karlsson, R., Roberts, A., Ridley, A., Pun, N., Khan, B., …Salanga, C. (2023). Chemokine CXCL4 interactions with extracellular matrix proteoglycans mediate widespread immune cell recruitment independent of chemokine receptors. Cell Reports, 111930 - ?. https://doi.org/10.1016/j.celrep.2022.111930

Acceptance Date	Dec 14, 2022
Publication Date	Jan 5, 2023
Journal	Cell Rep
Print ISSN	2211-1247
Publisher	Cell Press
Pages	111930 - ?
DOI	https://doi.org/10.1016/j.celrep.2022.111930
Publisher URL	https://www.cell.com/cell-reports/fulltext/S2211-1247(22)01831-9#%20