title: P-Rex and Vav Rac-GEFs in platelets control leukocyte recruitment to sites of inflammation.
abstract: The small GTPase Rac is required for neutrophil recruitment during inflammation, but its guanine-nucleotide exchange factor (GEF) activators seem dispensable for this process, which led us to investigate the possibility of cooperation between Rac-GEF families. Thioglycollate-induced neutrophil recruitment into the peritoneum was more severely impaired in P-Rex1(-/-) Vav1(-/-) (P1V1) or P-Rex1(-/-) Vav3(-/-) (P1V3) mice than in P-Rex null or Vav null mice, suggesting cooperation between P-Rex and Vav Rac-GEFs in this process. Neutrophil transmigration and airway infiltration were all but lost in P1V1 and P1V3 mice during lipopolysaccharide (LPS)-induced pulmonary inflammation, with altered intercellular adhesion molecule 1-dependent slow neutrophil rolling and strongly reduced L- and E-selectin-dependent adhesion in airway postcapillary venules. Analysis of adhesion molecule expression, neutrophil adhesion, spreading, and migration suggested that these defects were only partially neutrophil-intrinsic and were not obviously involving vascular endothelial cells. Instead, P1V1 and P1V3 platelets recapitulated the impairment of LPS-induced intravascular neutrophil adhesion and recruitment, showing P-Rex and Vav expression in platelets to be crucial. Similarly, during ovalbumin-induced allergic inflammation, pulmonary recruitment of P1V1 and P1V3 eosinophils, monocytes, and lymphocytes was compromised in a platelet-dependent manner, and airway inflammation was essentially abolished, resulting in improved airway responsiveness. Therefore, platelet P-Rex and Vav family Rac-GEFs play important proinflammatory roles in leukocyte recruitment.
authors.affiliation: Signalling Programme, Babraham Institute, Cambridge, United Kingdom; and.
authors.forename: Dingxin
authors.initials: D
authors.lastname: Pan
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, United Kingdom.
authors.forename: Richard T
authors.initials: RT
authors.lastname: Amison
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, United Kingdom.
authors.forename: Yanira
authors.initials: Y
authors.lastname: Riffo-Vasquez
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, United Kingdom.
authors.forename: Domenico
authors.initials: D
authors.lastname: Spina
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, United Kingdom.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Cleary
authors.affiliation: Signalling Programme, Babraham Institute, Cambridge, United Kingdom; and.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Wakelam
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, United Kingdom.
authors.forename: Clive P
authors.initials: CP
authors.lastname: Page
authors.affiliation: Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King's College London, United Kingdom.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Pitchford
authors.affiliation: Signalling Programme, Babraham Institute, Cambridge, United Kingdom; and.
authors.forename: Heidi C E
authors.initials: HC
authors.lastname: Welch
mesh_terms: D000208:Acute Disease; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism*; D002448:Cell Adhesion / Q000235:genetics; D002634:Chemotaxis, Leukocyte / Q000235:genetics*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D007249:Inflammation / Q000235:genetics* / Q000276:immunology*; D008070:Lipopolysaccharides; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics; D011014:Pneumonia / Q000235:genetics / Q000276:immunology; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics* / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D008070:Lipopolysaccharides; C511197:PREX1 protein, mouse; D051567:Proto-Oncogene Proteins c-vav; C496622:Vav3 protein, mouse