Glycosaminoglycan Interactions Fine-Tune Chemokine-Mediated Neutrophil Trafficking: Structural Insights and Molecular Mechanisms

Abstract

Circulating neutrophils, rapidly recruited in response to microbial infection, form the first line in host defense. Humans express ~50 chemokines, of which a subset of seven chemokines, characterized by the conserved "Glu-Leu-Arg" motif, mediate neutrophil recruitment. Neutrophil-activating chemokines (NACs) share similar structures, exist as monomers and dimers, activate the CXCR2 receptor on neutrophils, and interact with tissue glycosaminoglycans (GAGs). Considering cellular assays have shown that NACs have similar CXCR2 activity, the question has been and remains, why do humans express so many NACs? In this review, we make the case that NACs are not redundant and that distinct GAG interactions determine chemokine-specific in vivo functions. Structural studies have shown that the GAG-binding interactions of NACs are distinctly different, and that conserved and specific residues in the context of structure determine geometries that could not have been predicted from sequences alone. Animal studies indicate recruitment profiles of monomers and dimers are distinctly different, monomer-dimer equilibrium regulates recruitment, and that recruitment profiles vary between chemokines and between tissues, providing evidence that GAG interactions orchestrate neutrophil recruitment. We propose in vivo GAG interactions impact several chemokine properties including gradients and lifetime, and that these interactions fine-tune and define the functional response of each chemokine that can vary between different cell and tissue types for successful resolution of inflammation.

Associations of CXCL1 gene 5’UTR variations with ovarian cancer

“…This finding provides novel insights into the special roles of CXCL1 factor for the pathogenesis, diagnosis and therapies of ovarian cancer. [47,48]. GAGs bind to a diversity of protein classes [49], so in order to interact with GAGs, the sequence of chemokine must determine the selectivity, affinity and geometry [50].…”

Associations of CXCL1 gene 5’UTR variations with ovarian cancer

“…Chemokines is exists as monomers and dimers in vivo. Its function is produced by binding to tissue glycosaminoglycans (GAGs) heparan sulfate (HS), chondroitin sulfate (CS) and dermatan sulfate (DS) [47,48]. GAGs is binding to a diversity of protein classes [49], so in order to interact with GAGs, the sequence of chemokine must play special roles in determining selectivity, affinity and geometry [50].…”

Associations of CXCL1 gene 5’UTR variations with ovarian cancer

“…Many chemokines exist as monomers or dimers in vivo. They function by binding to tissue glycosaminoglycans (GAGs) heparan sulfate (HS), chondroitin sulfate (CS) or dermatan sulfate (DS) [47,48]. GAGs bind to a diversity of protein classes [49], so in order to interact with GAGs, the sequence of chemokine must determine the selectivity, affinity and geometry [50].…”