المؤلفون: Boras, Mark, Volmering, Stephanie, Bokemeyer, Arne, Rossaint, Jan, Block, Helena, Bardel, Bernadette, Van Marck, Veerle, Heitplatz, Barbara, Kliche, Stefanie, Reinhold, Annegret, Lowell, Clifford, Zarbock, Alexander

المصدر: Journal of Experimental Medicine. 214(3)

مصطلحات موضوعية: Underpinning research, Aetiology, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Inflammatory and immune system, Animals, CD18 Antigens, Cell Adhesion, Chemotaxis, Leukocyte, Cytoskeletal Proteins, E-Selectin, Intracellular Signaling Peptides and Proteins, Macrophage-1 Antigen, Mice, Mice, Inbred C57BL, Neutrophil Infiltration, Neutrophils, Protein Multimerization, Talin, Wiskott-Aldrich Syndrome Protein, src Homology Domains, Medical and Health Sciences, Immunology

الوصف: Integrin activation is required for neutrophil functions. Impaired integrin activation on neutrophils is the hallmark of leukocyte adhesion deficiency (LAD) syndrome in humans, characterized by impaired leukocyte recruitment and recurrent infections. The Src kinase-associated phosphoprotein 2 (Skap2) is involved in integrin functions in different leukocyte subtypes. However, the role of Skap2 in β2 integrin activation and neutrophil recruitment is unknown. In this study, we demonstrate the crucial role of Skap2 in regulating actin polymerization and binding of talin-1 and kindlin-3 to the β2 integrin cytoplasmic domain, thereby being indispensable for β2 integrin activation and neutrophil recruitment. The direct interaction of Skap2 with the Wiskott-Aldrich syndrome protein via its SH3 domain is critical for integrin activation and neutrophil recruitment in vivo. Furthermore, Skap2 regulates integrin-mediated outside-in signaling events and neutrophil functions. Thus, Skap2 is essential to activate the β2 integrins, and loss of Skap2 function is sufficient to cause a LAD-like phenotype in mice.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/6s64f9ttTest

المؤلفون: Block, Helena, Herter, Jan M, Rossaint, Jan, Stadtmann, Anika, Kliche, Stefanie, Lowell, Clifford A, Zarbock, Alexander

المصدر: Journal of Experimental Medicine. 209(2)

مصطلحات موضوعية: Biomedical and Clinical Sciences, Health Sciences, Kidney Disease, Aetiology, 2.1 Biological and endogenous factors, Adaptor Proteins, Signal Transducing, Agammaglobulinaemia Tyrosine Kinase, Animals, Cell Line, Tumor, Class Ib Phosphatidylinositol 3-Kinase, E-Selectin, Genetic Vectors, Humans, Integrins, Kidney, Leukocyte Rolling, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neutrophils, Peritonitis, Phospholipase C gamma, Phosphoproteins, Protein-Tyrosine Kinases, Reperfusion Injury, Retroviridae, Thioglycolates, Transduction, Genetic, Medical and Health Sciences, Immunology, Biomedical and clinical sciences, Health sciences

الوصف: 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.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0q54v5rwTest

المؤلفون: Block, Helena, Herter, Jan, Rossaint, Jan, Stadtmann, Anika, Kliche, Stefanie, Lowell, Clifford, Zarbock, Alexander

المصدر: Journal of Experimental Medicine. 209(2)

مصطلحات موضوعية: Adaptor Proteins, Signal Transducing, Agammaglobulinaemia Tyrosine Kinase, Animals, Cell Line, Tumor, Class Ib Phosphatidylinositol 3-Kinase, E-Selectin, Genetic Vectors, Humans, Integrins, Kidney, Leukocyte Rolling, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neutrophils, Peritonitis, Phospholipase C gamma, Phosphoproteins, Protein-Tyrosine Kinases, Reperfusion Injury, Retroviridae, Thioglycolates, Transduction, Genetic

الوصف: 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.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/0q54v5rwTest