| First Author | Johnson JL | Year | 2011 |
| Journal | Infect Immun | Volume | 79 |
| Issue | 9 | Pages | 3607-18 |
| PubMed ID | 21746860 | Mgi Jnum | J:175690 |
| Mgi Id | MGI:5287051 | Doi | 10.1128/IAI.05043-11 |
| Citation | Johnson JL, et al. (2011) Increased survival and reduced neutrophil infiltration of the liver in rab27a- but not munc13-4-deficient mice in lipopolysaccharide-induced systemic inflammation. Infect Immun 79(9):3607-18 |
| abstractText | 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-alpha) 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. |
