A fundamental role of mAbp1 in neutrophils: impact on β(2) integrin-mediated phagocytosis and adhesion in vivo Journal Article

Author(s): Schymeinsky, Jürgen; Gerstl, Ronald; Mannigel, Ingrid; Niedung, Katy; Frommhold, David; Panthel, Klaus; Heesemann, Jürgen; Sixt, Michael; Quast, Thomas; Kolanus, Waldemar; Mocsai, Attila; Wienands, Jürgen; Sperandio, Markus; Walzog, Barbara
Article Title: A fundamental role of mAbp1 in neutrophils: impact on β(2) integrin-mediated phagocytosis and adhesion in vivo
Abstract: The mammalian actin-binding protein 1 (mAbp1, Hip-55, SH3P7) is phosphorylated by the nonreceptor tyrosine kinase Syk that has a fundamental effect for several beta(2) integrin (CD11/CD18)-mediated neutrophil functions. Live cell imaging showed a dynamic enrichment of enhanced green fluorescence protein-tagged mAbp1 at the phagocytic cup of neutrophil-like differentiated HL-60 cells during beta(2) integrin-mediated phagocytosis of serum-opsonized Escherichia coli. The genetic absence of Syk or its pharmacologic inhibition using piceatannol abrogated the proper localization of mAbp1 at the phagocytic cup. The genetic absence or down-regulation of mAbp1 using the RNA interference technique significantly compromised beta(2) integrin-mediated phagocytosis of serum-opsonized E coli or Salmonella typhimurium in vitro as well as clearance of S typhimurium infection in vivo. Moreover, the genetic absence of mAbp1 almost completely abrogated firm neutrophil adhesion under physiologic shear stress conditions in vitro as well as leukocyte adhesion and extravasation in inflamed cremaster muscle venules of mice treated with tumor-necrosis factor alpha. Functional analysis showed that the down-regulation of mAbp1 diminished the number of beta(2) integrin clusters in the high-affinity conformation under flow conditions. These unanticipated results define mAbp1 as a novel molecular player in integrin biology that is critical for phagocytosis and firm neutrophil adhesion under flow conditions.
Keywords: Animals; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Antigens, CD18/*physiology; Cell Adhesion/physiology; Escherichia coli/pathogenicity; HL-60 Cells; Intracellular Signaling Peptides and Proteins/deficiency/genetics/metabolism; Mice, Inbred BALB C; Mice, Mutant Strains; Microfilament Proteins/antagonists & inhibitors/deficiency/genetics/*physiology; Neutrophils/*physiology; Phagocytosis/physiology; Protein-Tyrosine Kinases/deficiency/genetics/metabolism; RNA Interference; Receptors, IgG/metabolism; Salmonella typhimurium/pathogenicity; src Homology Domains/genetics/*physiology
Journal Title: Blood
Volume: 114
Issue 19
ISSN: 1528-0020
Publisher: American Society of Hematology  
Publication Place: United States
Date Published: 2009-11-05
Start Page: 4209
End Page: 4220
DOI: 10.1182/blood-2009-02-206169
Open access: no