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Signalling mechanisms for toll-like receptor-activated neutrophil exocytosis: Key roles for interleukin-1-receptor-associated kinase-4 and phosphatidylinositol 3-kinase but not toll/il-1 receptor (tir) domain-containing adaptor inducing ifn-beta (trif)

Academic Article
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Overview

authors

  • Brzezinska, A. A.
  • Johnson, J. L.
  • Munafo, D. B.
  • Ellis, B. A.
  • Catz, Sergio

publication date

  • July 2009

journal

  • Immunology  Journal

abstract

  • Lipopolysaccharide (LPS) stimulates exocytosis in neutrophils. The signalling molecules involved in the regulation of this mechanism are currently unknown. Using neutrophils from interleukin-1-receptor-associated kinase (IRAK)-4- and Toll/IL-1 receptor (TIR) domain-containing adaptor inducing IFN-beta (TRIF)-deficient mice, we dissected the signalling pathways that control exocytosis. We analysed exocytosis of peroxidase-negative and azurophilic granules by following the mobilization of the beta2-integrin subunit CD11b and myeloperoxidase (MPO)-containing granules, respectively. IRAK-4-null neutrophils showed marked defects in both peroxidase-negative and azurophilic granule exocytosis in response to LPS. In contrast, the exocytic response to LPS of TRIF-deficient neutrophils was not different from that of wild-type cells. No differences were observed in the exocytosis of secretory organelles between IRAK-4-null and wild-type neutrophils when they were stimulated with the phorbol ester phorbol 12-myristate 13-acetate (PMA). Electron microscopy analysis showed that no morphological abnormalities were present in the granules of IRAK-4-deficient neutrophils, suggesting that the lack of exocytic response to LPS is not attributable to developmental abnormalities. Using pharmacological inhibitors, we found that p38 mitogen-activated protein kinase (p38MAPK) is essential for the exocytosis of all neutrophil secretory organelles in response to LPS. Interestingly, we found that phosphatidylinositol 3-kinase (PI3K) is essential for azurophilic granule exocytosis but not for the mobilization of other neutrophil granules in response to LPS. Azurophilic granule exocytosis in response to Listeria monocytogenes was dependent on PI3K but not IRAK-4 activity, suggesting that alternative signalling pathways are activated in IRAK-4-deficient neutrophils exposed to whole bacteria. Our results identified IRAK-4, p38MAPK and PI3K as important regulatory components with different roles in the signalling pathways that control Toll-like receptor ligand-triggered neutrophil exocytosis.

subject areas

  • Adaptor Proteins, Vesicular Transport
  • Animals
  • Blood Bactericidal Activity
  • Cytoplasmic Granules
  • Escherichia coli
  • Exocytosis
  • Interleukin-1 Receptor-Associated Kinases
  • Lipopolysaccharides
  • Mice
  • Mice, Knockout
  • Microscopy, Electron
  • Neutrophils
  • Organelles
  • Oxidative Stress
  • Phosphatidylinositol 3-Kinases
  • Signal Transduction
  • Staphylococcus aureus
  • p38 Mitogen-Activated Protein Kinases
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Research

keywords

  • MyD88
  • granulocyte
  • inflammation
  • p38 mitogen-activated protein kinase
  • secretion
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Identity

PubMed Central ID

  • PMC2712107

International Standard Serial Number (ISSN)

  • 0019-2805

Digital Object Identifier (DOI)

  • 10.1111/j.1365-2567.2008.02980.x

PubMed ID

  • 19019092
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Additional Document Info

start page

  • 386

end page

  • 397

volume

  • 127

issue

  • 3

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