P-Rex1 regulates neutrophil function

TY - JOUR

T1 - P-Rex1 regulates neutrophil function

AU - Welch, H C E

AU - Condliffe, A M

AU - Milne, L J

AU - Ferguson, G J

AU - Hill, K

AU - Webb, L M C

AU - Okkenhaug, K

AU - Coadwell, W J

AU - Andrews, S R

AU - Thelen, M

AU - Jones, G E

AU - Hawkins, P T

AU - Stephens, L R

PY - 2005/10/25

Y1 - 2005/10/25

N2 - 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 P13K 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 P13K 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

AB - 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 P13K 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 P13K 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

U2 - 10.1016/j.cub.2005.09.050

DO - 10.1016/j.cub.2005.09.050

M3 - Article

SN - 1879-0445

VL - 15

SP - 1867

EP - 1873

JO - Current Biology

JF - Current Biology

IS - 20

ER -