Chemokine-matrix Interactions Promote Immune Cell Accumulation Independent of Chemokine Receptors

The chemokine CXCL4 is also known as platelet factor 4 (PF4), because: it is released from alpha-granules of activated platelets during platelet aggregation, and promotes blood coagulation by moderating the effects of heparin-like molecules. Due to these roles, it is predicted to play a role in wound repair and inflammation. It is usually found in a complex with proteoglycan (Wikipedia). CXCL4 binds heparin and extracellular matrix glycosaminoglycans with very high affinity and self-associates to form a tetrameric structure that is unusual in the chemokine family, whereas most CXC and CC chemokines form distinct dimeric structures. CXCL4 release promotes leukocyte recruitment, which would not be unusual for a chemokine - except that CXCL4 activates none of the G protein-coupled receptors that respond to chemokines, and this is the mechanism by which nearly all chemokines drive cell migration.


A new Cell Reports paper by scientists and collaborators of the Dyer research group at the University of Manchester resolves this longstanding chemokine conundrum using biophysical, in vitro, and in vivo techniques to determine the mechanism underlying CXCL4-mediated leukocyte recruitment. Their in vivo data are compelling: injection of CXCL4 protein in an air pouch model of leukocyte recruitment drew a surprisingly wide range of different leukocyte types, including neutrophils, eosinophils, monocytes, dendritic cells, and T cells. The authors ultimately concluded that leukocyte infiltration was dependent on CXCL4 binding to extracellular matrix heparin sulfate, rather than binding to a cell surface receptor. In particular, they showed that CXCL4 cross-linking of glycosaminoglycans produces endothelial cell signaling that regulate leukocyte recruitment. 

As noted in the STAR*Methods, several chemokines from the Protein Foundry catalog and a custom-produced CXCL4 variant protein were used in the experiments reported in this paper. 

Congratulations to Dr. Dyer and his team for publishing this groundbreaking study on novel effects on endothelial function by an unusual member of the chemokine family, and thank you for choosing Protein Foundry to provide key materials for your research!