How do chemokines navigate neutrophils to the target site

Dissecting the structural mechanisms and signaling pathways

Krishna Rajarathnam, Michael Schnoor, Ricardo M. Richardson, Sudarshan Rajagopal

Research output: Contribution to journalReview article

6 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)69-80
Number of pages12
JournalCellular Signalling
Volume54
DOIs
StatePublished - Feb 1 2019

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Arrestin
Chemokines
GTP-Binding Proteins
Neutrophils
Interleukin-8B Receptors
Interleukin-8A Receptors
Chemokine CXCL1
Chemokine CXCL2
Neutrophil Activation
Mitogen-Activated Protein Kinase Kinases
Type C Phospholipases
Protein-Tyrosine Kinases
Ligands
Infection

ASJC Scopus subject areas

  • Cell Biology

Cite this

How do chemokines navigate neutrophils to the target site : Dissecting the structural mechanisms and signaling pathways. / Rajarathnam, Krishna; Schnoor, Michael; Richardson, Ricardo M.; Rajagopal, Sudarshan.

In: Cellular Signalling, Vol. 54, 01.02.2019, p. 69-80.

Research output: Contribution to journalReview article

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