title: The Neutrophil Btk Signalosome Regulates Integrin Activation during Sterile Inflammation.
abstract: 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.
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Volmering
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster, Germany.
authors.forename: Helena
authors.initials: H
authors.lastname: Block
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Boras
authors.affiliation: Department of Laboratory Medicine and the Program in Immunology, University of California, 513 Parnassus Ave, MSB-1058, San Francisco, CA 94143-0451, USA.
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Lowell
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University of Münster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Münster, Germany. Electronic address: zarbock@uni-muenster.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D005434:Flow Cytometry; D007249:Inflammation; D016023:Integrins / Q000276:immunology / Q000378:metabolism*; D008107:Liver Diseases / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000276:immunology; D009336:Necrosis / Q000276:immunology; D020556:Neutrophil Infiltration / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000276:immunology* / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D016023:Integrins; D009240:N-Formylmethionine Leucyl-Phenylalanine; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625951:Btk protein, mouse
keywords: Btk; Src family kinases; WASp; fMLF; integrin; phospholipase C; signaling