title: Notch signaling mediates granulocyte-macrophage colony-stimulating factor priming-induced transendothelial migration of human eosinophils.
abstract: BACKGROUND
  Priming with cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances eosinophil migration and exacerbates the excessive accumulation of eosinophils within the bronchial mucosa of asthmatics. However, mechanisms that drive GM-CSF priming are incompletely understood. Notch signaling is an evolutionarily conserved pathway that regulates cellular processes, including migration, by integrating exogenous and cell-intrinsic cues. This study investigates the hypothesis that the priming-induced enhanced migration of human eosinophils requires the Notch signaling pathway.
  
  
  METHODS
  Using pan Notch inhibitors and newly developed human antibodies that specifically neutralize Notch receptor 1 activation, we investigated a role for Notch signaling in GM-CSF-primed transmigration of human blood eosinophils in vitro and in the airway accumulation of mouse eosinophils in vivo.
  
  
  RESULTS
  Notch receptor 1 was constitutively active in freshly isolated human blood eosinophils, and inhibition of Notch signaling or specific blockade of Notch receptor 1 activation during GM-CSF priming impaired priming-enhanced eosinophil transendothelial migration in vitro. Inclusion of Notch signaling inhibitors during priming was associated with diminished ERK phosphorylation, and ERK-MAPK activation was required for GM-CSF priming-induced transmigration. In vivo in mice, eosinophil accumulation within allergic airways was impaired following systemic treatment with Notch inhibitor, or adoptive transfer of eosinophils treated ex vivo with Notch inhibitor.
  
  
  CONCLUSIONS
  These data identify Notch signaling as an intrinsic pathway central to GM-CSF priming-induced eosinophil tissue migration.
authors.affiliation: Division of Allergy and Inflammation, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: L Y
authors.initials: LY
authors.lastname: Liu
authors.affiliation: Division of Allergy and Inflammation, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: H
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Allergy and Inflammation, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: J J
authors.initials: JJ
authors.lastname: Xenakis
authors.affiliation: Division of Allergy and Inflammation, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: L A
authors.initials: LA
authors.lastname: Spencer
mesh_terms: D019264:Adoptive Transfer; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D004804:Eosinophils / Q000187:drug effects / Q000502:physiology*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D051881:Receptor, Notch1 / Q000378:metabolism; D051880:Receptors, Notch; D012130:Respiratory Hypersensitivity / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects
chemical_list: D051881:Receptor, Notch1; D051880:Receptors, Notch; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D053829:Amyloid Precursor Protein Secretases
keywords: Notch pathway; asthma; cell migration; cytokine priming; γ-secretase
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