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Notch signaling mediates granulocyte‐macrophage colony‐stimulating factor priming‐induced transendothelial migration of human eosinophils
Author(s) -
Liu L.Y.,
Wang H.,
Xenakis J. J.,
Spencer L. A.
Publication year - 2015
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/all.12624
Subject(s) - notch signaling pathway , priming (agriculture) , eosinophil , microbiology and biotechnology , immunology , biology , mapk/erk pathway , signal transduction , botany , germination , asthma
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.