P-Rex1 regulates neutrophil function.
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.
Welch
Heidi C E
HC
Inositide Laboratory, The Babraham Institute, Babraham Research Campus, Cambridge CB2 4AT, United Kingdom.
Condliffe
Alison M
AM
Milne
Laura J
LJ
Ferguson
G John
GJ
Hill
Kirsti
K
Webb
Louise M C
LM
Okkenhaug
Klaus
K
Coadwell
W John
WJ
Andrews
Simon R
SR
Thelen
Marcus
M
Jones
Gareth E
GE
Hawkins
Phillip T
PT
Stephens
Len R
LR
D000199:Actins / Q000378:metabolism; D000818:Animals; D015550:Cell Degranulation / Q000502:physiology*; D002633:Chemotaxis / Q000502:physiology*; D003001:Cloning, Molecular; D004789:Enzyme Activation / Q000502:physiology; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009479:Neuropeptides / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism* / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein
D000199:Actins; D020662:Guanine Nucleotide Exchange Factors; D009479:Neuropeptides; D017382:Reactive Oxygen Species; D043562:Receptors, G-Protein-Coupled; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097766:RAC2 GTP-Binding Protein; C511197:PREX1 protein, mouse; C484602:Rac1 protein, mouse