title: Mutation in the CD45 inhibitory wedge modulates integrin activation and leukocyte recruitment during inflammation.
abstract: Neutrophil recruitment to the site of inflammation plays a pivotal role in host defense. Src family kinases (SFKs) activation is required for integrin and chemokine signaling as well as immune cell function. The receptor-like protein tyrosine phosphatase CD45 positively regulates chemoattractant signaling acting on SFK activity. To further investigate the role of CD45 in neutrophil recruitment and function, we analyzed transgenic mice carrying a single point mutation (CD45E613R), which constitutively activates CD45. By using intravital microscopy experiments, we demonstrated that different steps of the leukocyte recruitment cascade were affected in CD45E613R mutant mice. The rolling velocity of CD45E613R mutant neutrophils was decreased compared with wild-type neutrophils that subsequently resulted in an increased number of adherent cells. The analysis of β2 integrins LFA-1 and macrophage-1 Ag (Mac-1) showed that in CD45E613R mutant neutrophils LFA-1 adhesiveness was impaired, and avidity was enhanced, whereas Mac-1 adhesiveness was increased. Because of the increased Mac-1 adhesiveness, neutrophil crawling was impaired in CD45E613R mutant compared with wild-type neutrophils. In an Escherichia coli lung infection model, CD45E613R mice displayed a decreased neutrophil recruitment into the alveolar compartment, which resulted in an increased number of CFUs in the lung. Our data demonstrate that the CD45E613R mutation modulates integrin activation and leukocyte recruitment during inflammation.
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital of Münster, 48149 Münster, Germany; andMax-Planck Institute for Molecular Biomedicine, 48149 Münster, Germany.
authors.forename: Giulia
authors.initials: G
authors.lastname: Germena
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital of Münster, 48149 Münster, Germany; andMax-Planck Institute for Molecular Biomedicine, 48149 Münster, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Volmering
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital of Münster, 48149 Münster, Germany; andMax-Planck Institute for Molecular Biomedicine, 48149 Münster, Germany.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Sohlbach
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital of Münster, 48149 Münster, Germany; andMax-Planck Institute for Molecular Biomedicine, 48149 Münster, Germany zarbock@uni-muenster.de.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D004926:Escherichia coli / Q000276:immunology; D004927:Escherichia coli Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017493:Leukocyte Common Antigens / Q000235:genetics / Q000276:immunology; D036904:Leukocyte Rolling / Q000235:genetics / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D018410:Pneumonia, Bacterial / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017354:Point Mutation
chemical_list: D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse