title: Increased survival and reduced neutrophil infiltration of the liver in Rab27a- but not Munc13-4-deficient mice in lipopolysaccharide-induced systemic inflammation.
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.
authors: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors: Jennifer L
authors: JL
authors: Johnson
authors: Hong
authors: H
authors: Hong
authors: Jlenia
authors: J
authors: Monfregola
authors: Sergio D
authors: SD
authors: Catz
mesh_terms: D000818:Animals; D040881:CD11a Antigen / Q000096:biosynthesis; D039481:CD11b Antigen / Q000096:biosynthesis; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D003594:Cytoplasmic Granules / Q000276:immunology; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D007249:Inflammation / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology*; D008099:Liver / Q000276:immunology*; D008168:Lung / Q000276:immunology; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009503:Neutropenia / Q000139:chemically induced; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000097:blood; D020691:rab GTP-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000075745:rab27 GTP-Binding Proteins
chemical_list: D040881:CD11a Antigen; D039481:CD11b Antigen; D015815:Cell Adhesion Molecules; D018960:Hyaluronan Receptors; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; C520225:Unc13d protein, mouse; D000075745:rab27 GTP-Binding Proteins; C512962:Rab27a protein, mouse; D020691:rab GTP-Binding Proteins