Chemokine CXCL4 interactions with extracellular matrix proteoglycans mediate wide-spread non-receptor mediated immune cell recruitment

Gray, Anna L.; Karlsson, Richard; Roberts, Abigail R E; Ridley, Amanda J L; Pun, Nabina; Hughes, Catherine E.; Medina-Ruiz, Laura; Birchenough, Holly L.; Salanga, Catherina L.; Yates, Edwin A.; Turnbull, Jeremy E.; Handel, Tracy M.; Graham, Gerry; Jowitt, Thomas A.; Schießl, Ingo; Richter, Ralf P.; Miller, Rebecca L.; Dyer, Douglas P.

doi:10.1101/2022.07.10.499282

Cited by 2 publications

(3 citation statements)

References 52 publications

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“…Although it makes sense that weaker (less-specific) interactions will facilitate localization, particularly in the context of the bloodstream, certain chemokines (e.g., CXCL4 (PF4)) bind with incredibly high affinity. Recent work has suggested that some chemokines like CXCL4 primarily function by binding to GAGs, rather than directly to chemokine receptors (107). This can be mediated by signaling through cell surface proteoglycans and/or remodeling the ECM glycocalyx to facilitate leukocyte-endothelial interactions (108).…”

Section: Ecm Regulation By Chemokines and Cytokinesmentioning

confidence: 99%

The extracellular matrix and the immune system: A mutually dependent relationship

Sutherland

Dyer

Allen

2023

Science

171

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For decades, immunologists have studied the role of circulating immune cells in host protection, with a more recent appreciation of immune cells resident within the tissue microenvironment and the intercommunication between nonhematopoietic cells and immune cells. However, the extracellular matrix (ECM), which comprises at least a third of tissue structures, remains relatively underexplored in immunology. Similarly, matrix biologists often overlook regulation of complex structural matrices by the immune system. We are only beginning to understand the scale at which ECM structures determine immune cell localization and function. Additionally, we need to better understand how immune cells dictate ECM complexity. This review aims to highlight the potential for biological discovery at the interface of immunology and matrix biology.

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Section: Ecm Regulation By Chemokines and Cytokinesmentioning

confidence: 99%

The extracellular matrix and the immune system: A mutually dependent relationship

Sutherland

Dyer

Allen

2023

Science

171

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“…GAG sulphation has previously been shown to drive interaction specificity with other chemokines, e.g., CCL2 and CXCL4( 17, 24 ). We, therefore, hypothesised that GAG sulphation points could produce further differentiation in binding to CXCL9, 10 or 11.…”

Section: Resultsmentioning

confidence: 99%

“…ECM GAGs are particularly present within the glycocalyx that lines the luminal endothelial surface within blood vessels but can also be found throughout tissues( 14 ). Chemokine:GAG interactions have been shown to be key for leukocyte recruitment in vivo as they facilitate endothelial retention of chemokines on the endothelium in the presence of blood flow( 15, 16 ) and in the case of CXCL4 may directly mediate its function( 17 ). However, specific comprehension of the role of chemokine:GAG interactions on the cell surface and within tissues in leukocyte recruitment is lacking.…”

Section: Introductionmentioning

confidence: 99%

Chemokines form complex signals during inflammation and disease that can be decoded by extracellular matrix proteoglycans

Ridley

Karlsson

et al. 2022

Preprint

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Chemokine driven leukocyte recruitment is a key component of the immune response and is central to a wide range of diseases. However, there has yet to be a clinically successful therapeutic approach that targets the chemokine system during inflammatory disease; possibly due to the supposed redundancy of the chemokine system. A range of recent studies have demonstrated that the chemokine system is in fact based on specificity of function. Here we have generated a resource to analyse chemokine gene (ligand and receptor) expression across different species, tissues and diseases; revealing complex expression patterns whereby multiple chemokine ligands that mediate recruitment of the same leukocyte type are expressed in the same context, e.g. the CXCR3 ligands CXCL9, 10 and 11. We use biophysical approaches to show that CXCL9, 10 and 11 have very different interactions with extracellular matrix glycosaminoglycans (GAGs) which is exacerbated by specific GAG sulphation. Finally, in vivo approaches demonstrate that GAG-binding is critical for CXCL9 driven recruitment of specific T cell subsets (e.g. CD4+) but not others (e.g. CD8+), independent of CXCR3 expression. Our data demonstrate that chemokine expression is complex and that multiple ligands are likely needed for robust leukocyte recruitment across tissues and diseases. We also demonstrate that ECM GAGs facilitate decoding of these complex chemokine signals so that they are either primarily presented on GAG-coated cell surfaces or remain more soluble. Our findings represent a new mechanistic understanding of chemokine mediated immune cell recruitment and identify novel avenues to target specific chemokines during inflammatory disease.

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Chemokine CXCL4 interactions with extracellular matrix proteoglycans mediate wide-spread non-receptor mediated immune cell recruitment

Cited by 2 publications

References 52 publications

The extracellular matrix and the immune system: A mutually dependent relationship

The extracellular matrix and the immune system: A mutually dependent relationship

Chemokines form complex signals during inflammation and disease that can be decoded by extracellular matrix proteoglycans

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