P-Rex1 regulates neutrophil function

Rac GTPases regulate cytoskeletal structure, gene expression, and reactive oxygen species (ROS) production [1, 2]. Rac2-deficient neutrophils cannot chemotax, produce RIDS, or degranulate upon G protein-coupled receptor (GPCR) activation [3-10]. Deficiency in PI3K gamma, an upstream regulator of Rac, causes a similar phenotype [11-13]. P-Rex1, a guanine-nucleotide exchange factor (GEF) for Rac [14], is believed to link GPCRs and PI3K gamma 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 lipopolysaccharicle (LPS)primed P-Rex1-1- neutrophils, but less affected in unprimed or TNF alpha-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 re-sponses. However, P-Rex1 is not an essential regulator of neutrophil chemotaxis and degranulation.