AL Gray
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
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.
Acceptance Date | Dec 14, 2022 |
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Publication Date | Jan 5, 2023 |
Publicly Available Date | Mar 29, 2024 |
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 |
Files
Cell Reports 2022 Dyer et al.pdf
(6.3 Mb)
PDF
Publisher Licence URL
https://creativecommons.org/licenses/by/4.0/
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