Chemokine CXCL1-Mediated Neutrophil Trafficking in the Lung: Role of CXCR2 Activation

Kirti V. Sawant, Renling Xu, Robert Cox, Hal Hawkins, Elena Sbrana, Deepthi Kolli, Roberto P. Garofalo, Krishna Rajarathnam

Research output: Contribution to journalArticle

38 Scopus citations

Abstract

The chemokine CXCL1 and its receptor CXCR2 play a crucial role in host immune response by recruiting and activating neutrophils for microbial killing at the tissue site. Dysregulation in this process has been implicated in collateral tissue damage causing disease. CXCL1 reversibly exists as monomers and dimers, and it has been proposed that distinct monomer and dimer activities and the monomer-dimer equilibrium regulate the neutrophil function. However, the molecular mechanisms linking the CXCL1/CXCR2 axis and the neutrophil 'beneficial' and 'destructive' phenotypes are not known. In this study, we characterized neutrophil trafficking and its consequence in the mouse lung by the CXCL1 wild type (WT), which exists as monomers and dimers, and by a nondissociating dimer. Whereas the WT, compared to the dimer, was more active at low doses, both the WT and the dimer elicited a large neutrophil efflux at high doses. Importantly, robust neutrophil recruitment elicited by the WT or dimer was not detrimental to lung tissue integrity and, further, could not be correlated to surface CXCR2 levels. We conclude that the CXCL1 monomer-dimer distribution and receptor interactions are highly coupled and regulate neutrophil trafficking and that injury in the context of disease is a consequence of inappropriate CXCR2 activation at the target tissue and not due to mechanical forces exerted by neutrophils during recruitment.

Original languageEnglish (US)
Pages (from-to)647-658
Number of pages12
JournalJournal of Innate Immunity
Volume7
Issue number6
DOIs
StatePublished - Oct 16 2015

Keywords

  • Monomer-dimer equilibrium
  • Neutrophils
  • Receptor signaling
  • Tissue injury

ASJC Scopus subject areas

  • Immunology and Allergy

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