title: Identification and characterization of a unique role for EDB fibronectin in phagocytosis.
abstract: Plasma fibronectin is a circulating protein that facilitates phagocytosis by connecting bacteria to immune cells. A fibronectin isoform, which includes a sequence of 90 AA called extra-domain B (EDB), is synthesized de novo at the messenger RNA (mRNA) level in immune cells, but the reason for its expression remains elusive. We detected an 80-fold increase in EDB-containing fibronectin in the cerebrospinal fluid of patients with bacterial meningitis that was most pronounced in staphylococcal infections. A role for this isoform in phagocytosis was further suggested by enhanced EDB fibronectin release after internalization of Staphylococcus aureus in vitro. Using transgenic mouse models, we established that immune cell production of fibronectin contributes to phagocytosis, more so than circulating plasma fibronectin, and that accentuated release of EDB-containing fibronectin by immune cells improved phagocytosis. In line with this, administration of EDB fibronectin enhanced in vitro phagocytosis to a larger extent than plasma fibronectin. This enhancement was mediated by αvβ3 integrin as shown using inhibitors or cells from β3 integrin knockout mice. Thus, we identified both a novel function for EDB fibronectin in augmenting phagocytosis over circulating plasma fibronectin, as well as the mediating receptor. Our data also establish for the first time, a direct role for β3 integrin in bacterial phagocytosis in mammals.
  
  
  
  • Fibronectin containing an extra domain called EDB is released in bacterial meningitis. • EDB-containing fibronectin enhances phagocytosis more than plasma fibronectin. • The enhancement is mediated by activation of αvβ3 integrin in the presence of EDB.
authors.affiliation: Max-Planck Institute of Biochemistry, 82152, Martinsried, Germany.|Institute of Immunology, University of Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Kraft
authors.affiliation: Max-Planck Institute of Biochemistry, 82152, Martinsried, Germany.|Institute of Immunology, University of Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Klemis
authors.affiliation: Max-Planck Institute of Biochemistry, 82152, Martinsried, Germany.|Institute of Immunology, University of Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Carla
authors.initials: C
authors.lastname: Sens
authors.affiliation: Department of Neurology, University of Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lenhard
authors.affiliation: Department of Neurology, University of Heidelberg, 69120, Heidelberg, Germany.|Department of Neurology, Krankenhaus Nordwest, 60488, Frankfurt, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Jacobi
authors.affiliation: Institute of Immunology, University of Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Samstag
authors.affiliation: Institute of Immunology, University of Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Wabnitz
authors.affiliation: Institute of Immunology, University of Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kirschfink
authors.affiliation: Institute of Immunology, University of Heidelberg, 69120, Heidelberg, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Wallich
authors.affiliation: Institute of Immunology, University of Heidelberg, 69120, Heidelberg, Germany.
authors.forename: G Maria
authors.initials: GM
authors.lastname: Hänsch
authors.affiliation: Max-Planck Institute of Biochemistry, 82152, Martinsried, Germany. inaam.nakchbandi@immu.uni-heidelberg.de.|Institute of Immunology, University of Heidelberg, 69120, Heidelberg, Germany. inaam.nakchbandi@immu.uni-heidelberg.de.
authors.forename: Inaam A
authors.initials: IA
authors.lastname: Nakchbandi
mesh_terms: D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D016022:Case-Control Studies; D005353:Fibronectins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D039661:Integrin beta3 / Q000378:metabolism; D016920:Meningitis, Bacterial / Q000175:diagnosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010587:Phagocytosis / Q000276:immunology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D055503:Protein Multimerization; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D000199:Actins; D005353:Fibronectins; D039661:Integrin beta3
keywords: Bacterial infection; Circulation; EDB; EIIIB; Fibronectin; Innate immunity; Phagocytosis; Plasma fibronectin; αvβ3 integrin