title: Crucial role of SLP-76 and ADAP for neutrophil recruitment in mouse kidney ischemia-reperfusion injury.
abstract: Neutrophils trigger inflammation-induced acute kidney injury (AKI), a frequent and potentially lethal occurrence in humans. Molecular mechanisms underlying neutrophil recruitment to sites of inflammation have proved elusive. In this study, we demonstrate that SLP-76 (SH2 domain-containing leukocyte phosphoprotein of 76 kD) and ADAP (adhesion and degranulation promoting adaptor protein) are involved in E-selectin-mediated integrin activation and slow leukocyte rolling, which promotes ischemia-reperfusion-induced AKI in mice. By using genetically engineered mice and transduced Slp76(-/-) primary leukocytes, we demonstrate that ADAP as well as two N-terminal-located tyrosines and the SH2 domain of SLP-76 are required for downstream signaling and slow leukocyte rolling. The Tec family kinase Bruton tyrosine kinase is downstream of SLP-76 and, together with ADAP, regulates PI3Kγ (phosphoinositide 3-kinase-γ)- and PLCγ2 (phospholipase Cγ2)-dependent pathways. Blocking both pathways completely abolishes integrin affinity and avidity regulation. Thus, SLP-76 and ADAP are involved in E-selectin-mediated integrin activation and neutrophil recruitment to inflamed kidneys, which may underlie the development of life-threatening ischemia-reperfusion-induced AKI in humans.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, University of Münster, 48149 Münster, Germany.
authors.forename: Helena
authors.initials: H
authors.lastname: Block
authors.forename: Jan M
authors.initials: JM
authors.lastname: Herter
authors.forename: Jan
authors.initials: J
authors.lastname: Rossaint
authors.forename: Anika
authors.initials: A
authors.lastname: Stadtmann
authors.forename: Stefanie
authors.initials: S
authors.lastname: Kliche
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D045744:Cell Line, Tumor; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism; D019040:E-Selectin / Q000378:metabolism; D005822:Genetic Vectors; D006801:Humans; D016023:Integrins / Q000378:metabolism; D007668:Kidney / Q000098:blood supply* / Q000276:immunology*; D036904:Leukocyte Rolling / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology*; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology; D051966:Phospholipase C gamma / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015427:Reperfusion Injury / Q000276:immunology*; D012190:Retroviridae; D013864:Thioglycolates / Q000633:toxicity; D014161:Transduction, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D019040:E-Selectin; C491468:Fyb protein, mouse; D016023:Integrins; D010750:Phosphoproteins; C092947:SLP-76 signal Transducing adaptor proteins; D013864:Thioglycolates; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse; D051966:Phospholipase C gamma