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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

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


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

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.

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

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