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

Krishna Rajarathnam, Krishna Mohan Sepuru, Prem Raj B. Joseph, Kirti V. Sawant, Aaron J. Brown

Research output: Contribution to journalReview article

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)229-239
Number of pages11
JournalJournal of Histochemistry and Cytochemistry
Volume66
Issue number4
DOIs
StatePublished - Apr 1 2018

Keywords

  • extracellular matrix
  • gradients
  • heparan sulfate
  • inflammation
  • innate immunity
  • leukocyte trafficking

ASJC Scopus subject areas

  • Anatomy
  • Histology

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