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.
journal_name
Infect Immunjournal_title
Infection and immunityauthors
Johnson JL,Hong H,Monfregola J,Catz SDdoi
10.1128/IAI.05043-11subject
Has Abstractpub_date
2011-09-01 00:00:00pages
3607-18issue
9eissn
0019-9567issn
1098-5522pii
IAI.05043-11journal_volume
79pub_type
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更新日期:1998-06-01 00:00:00
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journal_title:Infection and immunity
pub_type: 杂志文章
doi:10.1128/IAI.59.11.4110-4116.1991
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journal_title:Infection and immunity
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doi:10.1128/IAI.61.10.4225-4231.1993
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journal_title:Infection and immunity
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abstract::Ferrets which had been orally dosed with 5 mg of Staphylococcal enterotoxin B (SEB) responded with an increase in subcutaneous temperature. At 75 min, the subcutaneous temperature was significantly higher (+ 0.9 degrees C +/- 0.38 degrees C, P < 0.007) than in control animals. Animals dosed with 1 or 2 mg of SEB respo...
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