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Increased survival and reduced neutrophil infiltration of the liver in Rab27a-but not Munc13-4-deficient mice in lipopolysaccharide-induced systemic inflammation

Academic Article
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Overview

authors

  • Johnson, J. L.
  • Hong, H.
  • Monfregola, J.
  • Catz, Sergio

publication date

  • September 2011

journal

  • Infection and Immunity  Journal

abstract

  • Genetic defects in the Rab27a or Munc13-4 gene lead to immunodeficiencies in humans, characterized by frequent viral and bacterial infections. However, the role of Rab27a and Munc13-4 in the regulation of systemic inflammation initiated by Gram-negative bacterium-derived pathogenic molecules is currently unknown. Using a model of lipopolysaccharide-induced systemic inflammation, we show that Rab27a-deficient (Rab27a(ash/ash)) mice are resistant to lipopolysaccharide (LPS)-induced death, while Munc13-4-deficient (Munc13-4(jinx/jinx)) mice show only moderate protection. Rab27a(ash/ash) but not Munc13-4(jinx/jinx) mice showed significantly decreased tumor necrosis factor alpha (TNF-α) plasma levels after LPS administration. Neutrophil sequestration in lungs from Rab27a(ash/ash) and Munc13-4(jinx/jinx) LPS-treated mice was similar to that observed for wild-type mice. In contrast, Rab27a- but not Munc13-4-deficient mice showed decreased neutrophil infiltration in liver and failed to undergo LPS-induced neutropenia. Decreased liver infiltration in Rab27a(ash/ash) mice was accompanied by lower CD44 but normal CD11a and CD11b expression in neutrophils. Both Rab27a- and Munc13-4-deficient mice showed decreased azurophilic granule secretion in vivo, suggesting that impaired liver infiltration and improved survival in Rab27a(ash/ash) mice is not fully explained by deficient exocytosis of this granule subset. Altogether, our data indicate that Rab27a but not Munc13-4 plays an important role in neutrophil recruitment to liver and LPS-induced death during endotoxemia, thus highlighting a previously unrecognized role for Rab27a in LPS-mediated systemic inflammation.

subject areas

  • Animals
  • Antigens, CD11a
  • Antigens, CD11b
  • Antigens, CD44
  • Cell Adhesion Molecules
  • Cytoplasmic Granules
  • Inflammation
  • Lipopolysaccharides
  • Liver
  • Lung
  • Lymphocyte Activation
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutropenia
  • Neutrophil Infiltration
  • Neutrophils
  • Tumor Necrosis Factor-alpha
  • rab GTP-Binding Proteins
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Identity

PubMed Central ID

  • PMC3165471

International Standard Serial Number (ISSN)

  • 0019-9567

Digital Object Identifier (DOI)

  • 10.1128/iai.05043-11

PubMed ID

  • 21746860
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Additional Document Info

start page

  • 3607

end page

  • 3618

volume

  • 79

issue

  • 9

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