Chemokine CXCL1 mediated neutrophil recruitment

Role of glycosaminoglycan interactions

Kirti V. Sawant, Krishna Mohan Poluri, Amit K. Dutta, Krishna Mohan Sepuru, Anna Troshkina, Roberto Garofalo, Krishna Rajarathnam

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The chemokine CXCL1/MGSA plays a pivotal role in the host immune response by recruiting and activating neutrophils for microbial killing at the tissue site. CXCL1 exists reversibly as monomers and dimers, and mediates its function by binding glycosaminoglycans (GAG) and CXCR2 receptor. We recently showed that both monomers and dimers are potent CXCR2 agonists, the dimer is the high-affinity GAG ligand, lysine and arginine residues located in two non-overlapping domains mediate GAG interactions, and there is extensive overlap between GAG and receptor-binding domains. To understand how these structural properties influence in vivo function, we characterized peritoneal neutrophil recruitment of a trapped monomer and trapped dimer and a panel of WT lysine/arginine to alanine mutants. Monomers and dimers were active, but WT was more active indicating synergistic interactions promote recruitment. Mutants from both domains showed reduced GAG heparin binding affinities and reduced neutrophil recruitment, providing compelling evidence that both GAG-binding domains mediate in vivo trafficking. Further, mutant of a residue that is involved in both GAG binding and receptor signaling showed the highest reduction in recruitment. We conclude that GAG interactions and receptor activity of CXCL1 monomers and dimers are fine-tuned to regulate neutrophil trafficking for successful resolution of tissue injury.

Original languageEnglish (US)
Article number33123
JournalScientific Reports
Volume6
DOIs
StatePublished - Sep 14 2016

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Chemokine CXCL1
Neutrophil Infiltration
Glycosaminoglycans
Lysine
Arginine
Neutrophils
Interleukin-8B Receptors
Alanine
Heparin
Ligands
glycosaminoglycan receptor
Wounds and Injuries

ASJC Scopus subject areas

  • General

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Chemokine CXCL1 mediated neutrophil recruitment : Role of glycosaminoglycan interactions. / Sawant, Kirti V.; Poluri, Krishna Mohan; Dutta, Amit K.; Sepuru, Krishna Mohan; Troshkina, Anna; Garofalo, Roberto; Rajarathnam, Krishna.

In: Scientific Reports, Vol. 6, 33123, 14.09.2016.

Research output: Contribution to journalArticle

Sawant, Kirti V. ; Poluri, Krishna Mohan ; Dutta, Amit K. ; Sepuru, Krishna Mohan ; Troshkina, Anna ; Garofalo, Roberto ; Rajarathnam, Krishna. / Chemokine CXCL1 mediated neutrophil recruitment : Role of glycosaminoglycan interactions. In: Scientific Reports. 2016 ; Vol. 6.
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