title: Myeloid-specific deletion of tumor suppressor PTEN augments neutrophil transendothelial migration during inflammation.
abstract: Phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) is a second messenger that is involved in a number of cell activities including cell growth, proliferation, and motility. PIP(3) is produced by PI3K and regulated by PTEN (phosphatase and tensin homolog deleted on chromosome 10) and SHIP lipid phosphatases. Evidence from our experiments shows that enhanced PIP(3) production results in elevated neutrophil recruitment under inflammatory conditions. However, the mechanism of this elevation is not well understood. We used intravital video microscopy to investigate neutrophil recruitment in the cremaster venules of wild-type and PTEN knockout (KO) mice. Neutrophil transmigration was augmented in PTEN KO mice 4 h after TNF-alpha intrascrotal injection. PTEN KO neutrophils also showed significantly enhanced transmigration 2 h after MIP-2 intrascrotal injection, an effect that dramatically decreased when PI3K or Src kinase inhibitor treatments preceded MIP-2 stimulation. Similarly, fMLP superfusion of the cremaster muscle lead to enhanced emigration in PTEN KO mice. The observed elevation in neutrophil emigration was likely caused by increased speed of crawling, crossing the venular wall, and migrating through the muscular tissue in PTEN KO mice because the effect of PTEN depletion on neutrophil rolling or adhesion was minimal. Interestingly, chemoattractant-induced release of gelatinase and elastase was also elevated in PTEN null neutrophils, providing a potential mechanism for the enhanced neutrophil migration in the PTEN KO mice. Collectively, these results demonstrate that PTEN deletion in neutrophils enhances their invasivity and recruitment to inflamed sites more likely by raising the cell physical capability to cross the vascular and tissue barriers.
authors.affiliation: Department of Lab Medicine, Children's Hospital, and.
authors.forename: Bara
authors.initials: B
authors.lastname: Sarraj
authors.forename: Steffen
authors.initials: S
authors.lastname: Massberg
authors.forename: Yitang
authors.initials: Y
authors.lastname: Li
authors.forename: Anongnard
authors.initials: A
authors.lastname: Kasorn
authors.forename: Kulandayan
authors.initials: K
authors.lastname: Subramanian
authors.forename: Fabien
authors.initials: F
authors.lastname: Loison
authors.forename: Leslie E
authors.initials: LE
authors.lastname: Silberstein
authors.forename: Ulrich
authors.initials: U
authors.lastname: von Andrian
authors.forename: Hongbo R
authors.initials: HR
authors.lastname: Luo
mesh_terms: D000818:Animals; D054426:Chemokine CXCL2 / Q000494:pharmacology; D004727:Endothelium / Q000502:physiology; D007249:Inflammation / Q000276:immunology*; D036904:Leukocyte Rolling; D051379:Mice; D018345:Mice, Knockout; D018715:Microscopy, Video; D018482:Muscle, Skeletal; D022423:Myeloid Cells; D020556:Neutrophil Infiltration; D051059:PTEN Phosphohydrolase / Q000172:deficiency*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D025521:Tumor Suppressor Proteins / Q000172:deficiency
chemical_list: D054426:Chemokine CXCL2; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse