P-Rex1 regulates neutrophil function

Curr Biol. 2005 Oct 25;15(20):1867-73. doi: 10.1016/j.cub.2005.09.050.

Abstract

Rac GTPases regulate cytoskeletal structure, gene expression, and reactive oxygen species (ROS) production. Rac2-deficient neutrophils cannot chemotax, produce ROS, or degranulate upon G protein-coupled receptor (GPCR) activation. Deficiency in PI3Kgamma, an upstream regulator of Rac, causes a similar phenotype. P-Rex1, a guanine-nucleotide exchange factor (GEF) for Rac, is believed to link GPCRs and PI3Kgamma to Rac-dependent neutrophil responses. We have investigated the functional importance of P-Rex1 by generating a P-Rex1(-/-) mouse. P-Rex1(-/-) mice are viable and healthy, with apparently normal leukocyte development, but with mild neutrophilia. In neutrophils from P-Rex1(-/-) mice, GPCR-dependent Rac2 activation is impaired, whereas Rac1 activation is less compromised. GPCR-dependent ROS formation is absent in lipopolysaccharide (LPS)-primed P-Rex1(-/-) neutrophils, but less affected in unprimed or TNFalpha-primed cells. Recruitment of P-Rex1(-/-) neutrophils to inflammatory sites is impaired. Surprisingly, chemotaxis of isolated neutrophils is only slightly reduced, with a mild defect in cell speed, but normal polarization and directionality. Secretion of azurophil granules is unaffected. In conclusion, P-Rex1 is an important regulator of neutrophil function by mediating a subset of Rac-dependent neutrophil responses. However, P-Rex1 is not an essential regulator of neutrophil chemotaxis and degranulation.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Cell Degranulation / physiology*
  • Chemotaxis / physiology*
  • Cloning, Molecular
  • Enzyme Activation / physiology
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Mice
  • Mice, Knockout
  • Neuropeptides / metabolism
  • Neutrophils / metabolism*
  • Neutrophils / physiology*
  • Reactive Oxygen Species / metabolism
  • Receptors, G-Protein-Coupled / metabolism
  • rac GTP-Binding Proteins / metabolism
  • rac1 GTP-Binding Protein

Substances

  • Actins
  • Guanine Nucleotide Exchange Factors
  • Neuropeptides
  • PREX1 protein, mouse
  • Rac1 protein, mouse
  • Reactive Oxygen Species
  • Receptors, G-Protein-Coupled
  • rac2 GTP-binding protein
  • rac GTP-Binding Proteins
  • rac1 GTP-Binding Protein