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Myeloid-Specific Deletion of Tumor Suppressor PTEN Augments Neutrophil Transendothelial Migration during Inflammation¹

Bara Sarraj^*, Steffen Massberg, Yitang Li^*, Anongnard Kasorn^*, Kulandayan Subramanian^*, Fabien Loison^*, Leslie E. Silberstein^*,, Ulrich von Andrian and Hongbo R. Luo^2,*,

^* Department of Lab Medicine, Children’s Hospital, and Department of Pathology, Harvard Medical School, Boston, MA 02115

Phosphatidylinositol 3,4,5-trisphosphate (PIP₃) is a second messenger that is involved in a number of cell activities including cell growth, proliferation, and motility. PIP₃ 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 PIP₃ 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- 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work is supported by Grant HL066987 from the National Institutes of Health Training Program (to B.S.). This work is also supported by Grants AI076471, HL085100, and GM076084 from the National Institutes of Health (to H.L.) and a Research Scholar Grant from the American Cancer Society.

² Address correspondence and reprint requests to Dr. Hongbo R. Luo, Department of Laboratory Medicine, Karp Family Research Building, Room 10214, Children’s Hospital, Boston, MA 02115. E-mail address: Hongbo.Luo{at}childrens.harvard.edu

³ Abbreviations used in this paper: PIP₃, phosphatidylinositol 3,4,5-trisphosphate; PIP₂, phosphatidylinositol 4,5-bisphosphate; PSGL, P-selectin glycoprotein ligand; IVM, intravital video microscopy; KO, knockout; WT, wild type; PTEN, phosphatase and tensin homolog deleted on chromosome 10.

⁴ The online version of this article contains supplemental material.