title: Cross-Talk between Shp1 and PIPKIγ Controls Leukocyte Recruitment.
abstract: Neutrophil recruitment to the site of inflammation plays a pivotal role in host defense. However, overwhelming activation and accumulation of neutrophils in the tissue may cause tissue damage and autoimmunity due to the release of cytokines, oxidants, and proteases. Neutrophil adhesion in acute inflammation is initiated by activation of αLβ2 (LFA-1), which can be induced by rolling on E-selectin (slowly) or by exposure to the chemokine CXCL1 (rapidly). Despite the clinical importance, cell-intrinsic molecular mechanisms of negative regulation of integrin adhesiveness and neutrophil recruitment are poorly understood. Mice deficient in the tyrosine phosphatase Src homology 2 domain-containing protein tyrosine phosphatase 1 (Shp1) show increased leukocyte adhesion, but the interpretation of these data is limited by the severe global phenotype of these mice. In this study, we used mice with global and myeloid-restricted deletion of Shp1 to study neutrophil arrest, adhesion, crawling, and transendothelial migration in vitro and in vivo. Shp1 deficiency results in increased neutrophil adhesion in vivo; however, neutrophil crawling, transmigration, and chemotaxis were reduced in these mice. Mechanistically, Shp1 binds and controls PIPKIγ activity and, thereby, modulates phosphatidylinositol (4,5)-bisphosphate levels and adhesion. Thus, Shp1 is involved in the deactivation of integrins and regulation of neutrophil recruitment into inflamed tissue.
authors.affiliation: Department of Anesthesiology, Intensive Care, and Pain Medicine, University of Münster, 48149 Münster, Germany; Max-Planck Institute for Molecular Biomedicine, 48149 Münster, Germany; and.
authors.forename: Anika
authors.initials: A
authors.lastname: Stadtmann
authors.affiliation: Department of Anesthesiology, Intensive Care, and Pain Medicine, University of Münster, 48149 Münster, Germany; Max-Planck Institute for Molecular Biomedicine, 48149 Münster, Germany; and.
authors.forename: Helena
authors.initials: H
authors.lastname: Block
authors.affiliation: Department of Anesthesiology, Intensive Care, and Pain Medicine, University of Münster, 48149 Münster, Germany; Max-Planck Institute for Molecular Biomedicine, 48149 Münster, Germany; and.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Volmering
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA 94143.
authors.forename: Clare
authors.initials: C
authors.lastname: Abram
authors.affiliation: Department of Anesthesiology, Intensive Care, and Pain Medicine, University of Münster, 48149 Münster, Germany; Max-Planck Institute for Molecular Biomedicine, 48149 Münster, Germany; and.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Sohlbach
authors.affiliation: Department of Anesthesiology, Intensive Care, and Pain Medicine, University of Münster, 48149 Münster, Germany; Max-Planck Institute for Molecular Biomedicine, 48149 Münster, Germany; and.
authors.forename: Mark
authors.initials: M
authors.lastname: Boras
authors.affiliation: Department of Laboratory Medicine, University of California, San Francisco, CA 94143.
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.affiliation: Department of Anesthesiology, Intensive Care, and Pain Medicine, University of Münster, 48149 Münster, Germany; Max-Planck Institute for Molecular Biomedicine, 48149 Münster, Germany; and zarbock@uni-muenster.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D054360:Chemokine CXCL1 / Q000276:immunology; D019040:E-Selectin / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D018922:HL-60 Cells; D006801:Humans; D007249:Inflammation / Q000276:immunology; D036904:Leukocyte Rolling / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology; D010716:Phosphatidylinositols / Q000096:biosynthesis / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D019040:E-Selectin; D016169:Lymphocyte Function-Associated Antigen-1; D010716:Phosphatidylinositols; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse