title: Leishmania promastigotes induce cytokine secretion in macrophages through the degradation of synaptotagmin XI.
abstract: Synaptotagmins (Syts) are type-I membrane proteins that regulate vesicle docking and fusion in processes such as exocytosis and phagocytosis. We recently discovered that Syt XI is a recycling endosome- and lysosome-associated protein that negatively regulates the secretion of TNF and IL-6. In this study, we show that Syt XI is directly degraded by the zinc metalloprotease GP63 and excluded from Leishmania parasitophorous vacuoles by the promastigotes surface glycolipid lipophosphoglycan. Infected macrophages were found to release TNF and IL-6 in a GP63-dependent manner. To demonstrate that cytokine release was dependent on GP63-mediated degradation of Syt XI, small interfering RNA-mediated knockdown of Syt XI before infection revealed that the effects of small interfering RNA knockdown and GP63 degradation were not cumulative. In mice, i.p. injection of GP63-expressing parasites led to an increase in TNF and IL-6 secretion and to an augmented influx of neutrophils and inflammatory monocytes to the inoculation site. Both of these cell types have been shown to be infection targets and aid in the establishment of infection. In sum, our data revealed that GP63 induces proinflammatory cytokine release and increases infiltration of inflammatory phagocytes. This study provides new insight on how Leishmania exploits the immune response to establish infection.
authors: Institut National de la Recherche Scientifique-Institut Armand-Frappier, Laval, Quebec H7V 1B7, Canada; Centre for Host-Parasite Interactions, Laval, Quebec H7V 1B7, Canada;
authors: Guillermo
authors: G
authors: Arango Duque
authors: Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan; and.
authors: Mitsunori
authors: M
authors: Fukuda
authors: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40508.
authors: Salvatore J
authors: SJ
authors: Turco
authors: Institut National de la Recherche Scientifique-Institut Armand-Frappier, Laval, Quebec H7V 1B7, Canada; Centre for Host-Parasite Interactions, Laval, Quebec H7V 1B7, Canada;
authors: Simona
authors: S
authors: Stäger
authors: Institut National de la Recherche Scientifique-Institut Armand-Frappier, Laval, Quebec H7V 1B7, Canada; Centre for Host-Parasite Interactions, Laval, Quebec H7V 1B7, Canada; albert.descoteaux@iaf.inrs.ca.
authors: Albert
authors: A
authors: Descoteaux
mesh_terms: D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D005260:Female; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D007891:Leishmania / Q000235:genetics / Q000276:immunology*; D007896:Leishmaniasis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000469:parasitology / Q000473:pathology; D008666:Metalloendopeptidases / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D050857:Synaptotagmins / Q000235:genetics / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology*
chemical_list: D015850:Interleukin-6; C494266:Syt11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D050857:Synaptotagmins; D008666:Metalloendopeptidases; C055146:glycoprotein gp63, Leishmania