Chemokine CXCL4 interactions with extracellular matrix proteoglycans mediate widespread immune cell recruitment independent of chemokine receptors
Gray, A.L. et al. (2023) Chemokine CXCL4 interactions with extracellular matrix proteoglycans mediate widespread immune cell recruitment independent of chemokine receptors. Cell Reports 42, 111930. DOI: 10.1016/j.celrep.2022.111930
White blood cells (leukocytes) can move from the vasculature into tissues during infection and are implicated in inflammatory disease. Chemokines play a central role in leukocyte migration to tissues, and as such, are targets for inflammation therapies. However, the authors note that currently developed therapeutics often fail, perhaps due to a lack of understanding of chemokine biology and function.
Chemokines are believed to work by binding to G-protein coupled receptors on leukocytes, activating integrin and forming strong attachment to cells lining the vasculature. Chemokine CXCL4 (platelet factor 4 or PF4) is produced by platelets and macrophages. It participates in leukocyte recruitment and has been implicated in disease, but doesn’t have a defined receptor, limiting the ability to develop therapeutics targeting this chemokine.
This study shows that CXCL4 promotes leukocyte adhesion to blood vessel lining, resulting in endothelial permeability and recruitment of additional immune cells. The researchers identified interaction of CXCL4 with glycocalyx (GAG) proteins on endothelial proteoglycans. The researchers further show that GAG sulfation patterns lend specificity to GAG:chemokine interactions, preventing redundancy.
Keywords: leukocyte migration, chemokine receptor, chemokine therapeutics, novel inflammation therapies, cxcl4
