TY - JOUR
T1 - P-Rex and Vav Rac-GEFs in platelets control leukocyte recruitment to sites of inflammation
AU - Pan, Dingxin
AU - Amison, Richard T.
AU - Riffo-Vasquez, Yanira
AU - Spina, Domenico
AU - Cleary, Simon J.
AU - Wakelam, Michael J.
AU - Page, Clive P.
AU - Pitchford, Simon C.
AU - Welch, Heidi C E
PY - 2015/2/12
Y1 - 2015/2/12
N2 - 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 peritoneu was more severely impaired in P-Rex1-/-Vav1-/-(P1V1) or P-Rex1-/-Vav32/2(P1V3) micethan 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 recruitmentofP1V1andP1V3eosinophils,monocytes,andlymphocyteswascompromisedin aplateletdependent 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.
AB - 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 peritoneu was more severely impaired in P-Rex1-/-Vav1-/-(P1V1) or P-Rex1-/-Vav32/2(P1V3) micethan 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 recruitmentofP1V1andP1V3eosinophils,monocytes,andlymphocyteswascompromisedin aplateletdependent 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.
UR - http://www.scopus.com/inward/record.url?scp=84923303152&partnerID=8YFLogxK
U2 - 10.1182/blood-2014-07-591040
DO - 10.1182/blood-2014-07-591040
M3 - Article
AN - SCOPUS:84923303152
SN - 0006-4971
VL - 125
SP - 1146
EP - 1158
JO - Blood
JF - Blood
IS - 7
ER -