How do chemokines navigate neutrophils to the target site: Dissecting the structural mechanisms and signaling pathways

Cell Signal. 2019 Feb:54:69-80. doi: 10.1016/j.cellsig.2018.11.004. Epub 2018 Nov 19.


Chemokines play crucial roles in combating microbial infection and initiating tissue repair by recruiting neutrophils in a timely and coordinated manner. In humans, no less than seven chemokines (CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8) and two receptors (CXCR1 and CXCR2) mediate neutrophil functions but in a context dependent manner. Neutrophil-activating chemokines reversibly exist as monomers and dimers, and their receptor binding triggers conformational changes that are coupled to G-protein and β-arrestin signaling pathways. G-protein signaling activates a variety of effectors including Ca2+ channels and phospholipase C. β-arrestin serves as a multifunctional adaptor and is coupled to several signaling hubs including MAP kinase and tyrosine kinase pathways. Both G-protein and β-arrestin signaling pathways play important non-overlapping roles in neutrophil trafficking and activation. Functional studies have established many similarities but distinct differences for a given chemokine and between chemokines at the level of monomer vs. dimer, CXCR1 vs. CXCR2 activation, and G-protein vs. β-arrestin pathways. We propose that two forms of the ligand binding two receptors and activating two signaling pathways enables fine-tuned neutrophil function compared to a single form, a single receptor, or a single pathway. We summarize the current knowledge on the molecular mechanisms by which chemokine monomers/dimers activate CXCR1/CXCR2 and how these interactions trigger G-protein/β-arrestin-coupled signaling pathways. We also discuss current challenges and knowledge gaps, and likely advances in the near future that will lead to a better understanding of the relationship between the chemokine-CXCR1/CXCR2-G-protein/β-arrestin axis and neutrophil function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Chemokines, CXC* / chemistry
  • Chemokines, CXC* / metabolism
  • GTP-Binding Proteins / metabolism*
  • Humans
  • Mice
  • Neutrophils* / cytology
  • Neutrophils* / metabolism
  • Protein Binding
  • Receptors, CXCR* / chemistry
  • Receptors, CXCR* / metabolism
  • Signal Transduction
  • beta-Arrestins / metabolism*


  • Chemokines, CXC
  • Receptors, CXCR
  • beta-Arrestins
  • GTP-Binding Proteins