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 V. Navarro, David Oupicky, Fei Sun, Chunying Li

Research output: Contribution to journalArticlepeer-review

45 Scopus citations


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
Issue number8
StatePublished - Feb 17 2012
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology


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