المؤلفون: Volmering, Stephanie, Block, Helena, Boras, Mark, Lowell, Clifford A, Zarbock, Alexander

المصدر: Immunity. 44(1)

مصطلحات موضوعية: Animals, Mice, Liver Diseases, Inflammation, Necrosis, N-Formylmethionine Leucyl-Phenylalanine, Integrins, Microscopy, Confocal, Flow Cytometry, Signal Transduction, Neutrophil Infiltration, Protein-Tyrosine Kinases, Btk, Src family kinases, WASp, fMLF, integrin, phospholipase C, signaling, Agammaglobulinaemia Tyrosine Kinase, Immunology

الوصف: Neutrophils are recruited from the blood to sites of sterile inflammation, where they are involved in wound healing but can also cause tissue damage. During sterile inflammation, necrotic cells release pro-inflammatory molecules including formylated peptides. However, the signaling pathway triggered by formylated peptides to integrin activation and leukocyte recruitment is unknown. By using spinning-disk confocal intravital microscopy, we examined the molecular mechanisms of leukocyte recruitment to sites of focal hepatic necrosis in vivo. We demonstrated that the Bruton's tyrosine kinase (Btk) was required for multiple Mac-1 activation events involved in neutrophil recruitment and functions during sterile inflammation triggered by fMLF. The Src family kinase Hck, Wiskott-Aldrich-syndrome protein, and phospholipase Cγ2 were also involved in this pathway required for fMLF-triggered Mac-1 activation and neutrophil recruitment. Thus, we have identified a neutrophil Btk signalosome that is involved in a signaling pathway triggered by formylated peptides leading to the selective activation of Mac-1 and neutrophil recruitment during sterile inflammation.

وصف الملف: application/pdf

الوصول الحر: https://escholarship.org/uc/item/4c56h6d5Test

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