A chemokine receptor CXCR2 macromolecular complex regulates neutrophil functions in inflammatory diseases

Yanning Wu, Shuo Wang, Shukkur M. Farooq, Marcello P. Castelvetere, Yuning Hou, Ji Liang Gao, Javier Navarro, David Oupicky, Fei Sun, Chunying Li

Research output: Contribution to journalArticle

42 Citations (Scopus)

Abstract

Inflammation plays an important role in a wide range of human diseases such as ischemia-reperfusion injury, arteriosclerosis, cystic fibrosis, inflammatory bowel disease, etc. Neutrophilic accumulation in the inflamed tissues is an essential component of normal host defense against infection, but uncontrolled neutrophilic infiltration can cause progressive damage to the tissue epithelium. The CXC chemokine receptor CXCR2 and its specific ligands have been reported to play critical roles in the pathophysiology of various inflammatory diseases. However, it is unclear howCXCR2is coupled specifically to its downstream signaling molecules and modulates cellular functions of neutrophils. Here we show that the PDZ scaffold protein NHERF1 couples CXCR2 to its downstream effector phospholipase C ( PLC)-β2, forming a macromolecular complex, through a PDZ-based interaction. We assembled a macromolecular complex of CXCR2•NHERF1•PLC-2 in vitro, and we also detected such a complex in neutrophils by co-immunoprecipitation. Wefurther observed that the CXCR2-containing macromolecular complex is critical for the CXCR2-mediated intracellular calcium mobilization and the resultant migration and infiltration of neutrophils, as disrupting the complex with a cell permeant CXCR2-specific peptide (containing the PDZ motif) inhibited intracellular calcium mobilization, chemotaxis, and transepithelial migration of neutrophils. Taken together, our data demonstrate a critical role of the PDZ-dependent CXCR2 macromolecular signaling complex in regulating neutrophil functions and suggest that targeting the CXCR2 multiprotein complex may represent a novel therapeutic strategy for certain inflammatory diseases.

Original languageEnglish (US)
Pages (from-to)5744-5755
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number8
DOIs
StatePublished - Feb 17 2012

Fingerprint

Macromolecular Substances
Chemokine Receptors
Neutrophils
Infiltration
CXCR Receptors
Tissue
Calcium
Transendothelial and Transepithelial Migration
Multiprotein Complexes
Neutrophil Infiltration
Arteriosclerosis
Type C Phospholipases
Chemotaxis
Reperfusion Injury
Inflammatory Bowel Diseases
Immunoprecipitation
Cystic Fibrosis
Scaffolds
Epithelium
Ligands

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Wu, Y., Wang, S., Farooq, S. M., Castelvetere, M. P., Hou, Y., Gao, J. L., ... Li, C. (2012). A chemokine receptor CXCR2 macromolecular complex regulates neutrophil functions in inflammatory diseases. Journal of Biological Chemistry, 287(8), 5744-5755. https://doi.org/10.1074/jbc.M111.315762

A chemokine receptor CXCR2 macromolecular complex regulates neutrophil functions in inflammatory diseases. / Wu, Yanning; Wang, Shuo; Farooq, Shukkur M.; Castelvetere, Marcello P.; Hou, Yuning; Gao, Ji Liang; Navarro, Javier; Oupicky, David; Sun, Fei; Li, Chunying.

In: Journal of Biological Chemistry, Vol. 287, No. 8, 17.02.2012, p. 5744-5755.

Research output: Contribution to journalArticle

Wu, Y, Wang, S, Farooq, SM, Castelvetere, MP, Hou, Y, Gao, JL, Navarro, J, Oupicky, D, Sun, F & Li, C 2012, 'A chemokine receptor CXCR2 macromolecular complex regulates neutrophil functions in inflammatory diseases', Journal of Biological Chemistry, vol. 287, no. 8, pp. 5744-5755. https://doi.org/10.1074/jbc.M111.315762
Wu, Yanning ; Wang, Shuo ; Farooq, Shukkur M. ; Castelvetere, Marcello P. ; Hou, Yuning ; Gao, Ji Liang ; Navarro, Javier ; Oupicky, David ; Sun, Fei ; Li, Chunying. / A chemokine receptor CXCR2 macromolecular complex regulates neutrophil functions in inflammatory diseases. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 8. pp. 5744-5755.
@article{3fc38c34217e4d5bb79c7e05e8a24df0,
title = "A chemokine receptor CXCR2 macromolecular complex regulates neutrophil functions in inflammatory diseases",
abstract = "Inflammation plays an important role in a wide range of human diseases such as ischemia-reperfusion injury, arteriosclerosis, cystic fibrosis, inflammatory bowel disease, etc. Neutrophilic accumulation in the inflamed tissues is an essential component of normal host defense against infection, but uncontrolled neutrophilic infiltration can cause progressive damage to the tissue epithelium. The CXC chemokine receptor CXCR2 and its specific ligands have been reported to play critical roles in the pathophysiology of various inflammatory diseases. However, it is unclear howCXCR2is coupled specifically to its downstream signaling molecules and modulates cellular functions of neutrophils. Here we show that the PDZ scaffold protein NHERF1 couples CXCR2 to its downstream effector phospholipase C ( PLC)-β2, forming a macromolecular complex, through a PDZ-based interaction. We assembled a macromolecular complex of CXCR2•NHERF1•PLC-2 in vitro, and we also detected such a complex in neutrophils by co-immunoprecipitation. Wefurther observed that the CXCR2-containing macromolecular complex is critical for the CXCR2-mediated intracellular calcium mobilization and the resultant migration and infiltration of neutrophils, as disrupting the complex with a cell permeant CXCR2-specific peptide (containing the PDZ motif) inhibited intracellular calcium mobilization, chemotaxis, and transepithelial migration of neutrophils. Taken together, our data demonstrate a critical role of the PDZ-dependent CXCR2 macromolecular signaling complex in regulating neutrophil functions and suggest that targeting the CXCR2 multiprotein complex may represent a novel therapeutic strategy for certain inflammatory diseases.",
author = "Yanning Wu and Shuo Wang and Farooq, {Shukkur M.} and Castelvetere, {Marcello P.} and Yuning Hou and Gao, {Ji Liang} and Javier Navarro and David Oupicky and Fei Sun and Chunying Li",
year = "2012",
month = "2",
day = "17",
doi = "10.1074/jbc.M111.315762",
language = "English (US)",
volume = "287",
pages = "5744--5755",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "8",

}

TY - JOUR

T1 - A chemokine receptor CXCR2 macromolecular complex regulates neutrophil functions in inflammatory diseases

AU - Wu, Yanning

AU - Wang, Shuo

AU - Farooq, Shukkur M.

AU - Castelvetere, Marcello P.

AU - Hou, Yuning

AU - Gao, Ji Liang

AU - Navarro, Javier

AU - Oupicky, David

AU - Sun, Fei

AU - Li, Chunying

PY - 2012/2/17

Y1 - 2012/2/17

N2 - Inflammation plays an important role in a wide range of human diseases such as ischemia-reperfusion injury, arteriosclerosis, cystic fibrosis, inflammatory bowel disease, etc. Neutrophilic accumulation in the inflamed tissues is an essential component of normal host defense against infection, but uncontrolled neutrophilic infiltration can cause progressive damage to the tissue epithelium. The CXC chemokine receptor CXCR2 and its specific ligands have been reported to play critical roles in the pathophysiology of various inflammatory diseases. However, it is unclear howCXCR2is coupled specifically to its downstream signaling molecules and modulates cellular functions of neutrophils. Here we show that the PDZ scaffold protein NHERF1 couples CXCR2 to its downstream effector phospholipase C ( PLC)-β2, forming a macromolecular complex, through a PDZ-based interaction. We assembled a macromolecular complex of CXCR2•NHERF1•PLC-2 in vitro, and we also detected such a complex in neutrophils by co-immunoprecipitation. Wefurther observed that the CXCR2-containing macromolecular complex is critical for the CXCR2-mediated intracellular calcium mobilization and the resultant migration and infiltration of neutrophils, as disrupting the complex with a cell permeant CXCR2-specific peptide (containing the PDZ motif) inhibited intracellular calcium mobilization, chemotaxis, and transepithelial migration of neutrophils. Taken together, our data demonstrate a critical role of the PDZ-dependent CXCR2 macromolecular signaling complex in regulating neutrophil functions and suggest that targeting the CXCR2 multiprotein complex may represent a novel therapeutic strategy for certain inflammatory diseases.

AB - Inflammation plays an important role in a wide range of human diseases such as ischemia-reperfusion injury, arteriosclerosis, cystic fibrosis, inflammatory bowel disease, etc. Neutrophilic accumulation in the inflamed tissues is an essential component of normal host defense against infection, but uncontrolled neutrophilic infiltration can cause progressive damage to the tissue epithelium. The CXC chemokine receptor CXCR2 and its specific ligands have been reported to play critical roles in the pathophysiology of various inflammatory diseases. However, it is unclear howCXCR2is coupled specifically to its downstream signaling molecules and modulates cellular functions of neutrophils. Here we show that the PDZ scaffold protein NHERF1 couples CXCR2 to its downstream effector phospholipase C ( PLC)-β2, forming a macromolecular complex, through a PDZ-based interaction. We assembled a macromolecular complex of CXCR2•NHERF1•PLC-2 in vitro, and we also detected such a complex in neutrophils by co-immunoprecipitation. Wefurther observed that the CXCR2-containing macromolecular complex is critical for the CXCR2-mediated intracellular calcium mobilization and the resultant migration and infiltration of neutrophils, as disrupting the complex with a cell permeant CXCR2-specific peptide (containing the PDZ motif) inhibited intracellular calcium mobilization, chemotaxis, and transepithelial migration of neutrophils. Taken together, our data demonstrate a critical role of the PDZ-dependent CXCR2 macromolecular signaling complex in regulating neutrophil functions and suggest that targeting the CXCR2 multiprotein complex may represent a novel therapeutic strategy for certain inflammatory diseases.

UR - http://www.scopus.com/inward/record.url?scp=84863158649&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863158649&partnerID=8YFLogxK

U2 - 10.1074/jbc.M111.315762

DO - 10.1074/jbc.M111.315762

M3 - Article

C2 - 22203670

AN - SCOPUS:84863158649

VL - 287

SP - 5744

EP - 5755

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 8

ER -