title: Pseudomonas aeruginosa pyocyanin induces neutrophil death via mitochondrial reactive oxygen species and mitochondrial acid sphingomyelinase.
abstract: OBJECTIVE
  Pulmonary infections with Pseudomonas aeruginosa are a serious clinical problem and are often lethal. Because many strains of P. aeruginosa are resistant to antibiotics, therapeutic options are limited. Neutrophils play an important role in the host's early acute defense against pulmonary P. aeruginosa. Therefore, it is important to define the mechanisms by which P. aeruginosa interacts with host cells, particularly neutrophils.
  
  
  RESULTS
  Here, we report that pyocyanin, a membrane-permeable pigment and toxin released by P. aeruginosa, induces the death of wild-type neutrophils; its interaction with the mitochondrial respiratory chain results in the release of reactive oxygen species (ROS), the activation of mitochondrial acid sphingomyelinase, the formation of mitochondrial ceramide, and the release of cytochrome c from mitochondria. A genetic deficiency in acid sphingomyelinase prevents both the activation of this pathway and pyocyanin-induced neutrophil death. This reduced death, on the other hand, is associated with an increase in the release of interleukin-8 from pyocyanin-activated acid sphingomyelinase-deficient neutrophils but not from wild-type cells.
  
  
  METHODS
  These studies identified the mechanisms by which pyocyanin induces the release of mitochondrial ROS and by which ROS induce neutrophil death via mitochondrial acid sphingomyelinase.
  
  
  CONCLUSIONS
  These findings demonstrate a novel mechanism of pyocyanin-induced death of neutrophils and show how this apoptosis balances innate immune reactions.
authors: 1 Department of Biology, University of Padova , Padova, Italy .
authors: Antonella
authors: A
authors: Managò
authors: Katrin Anne
authors: KA
authors: Becker
authors: Alexander
authors: A
authors: Carpinteiro
authors: Barbara
authors: B
authors: Wilker
authors: Matthias
authors: M
authors: Soddemann
authors: Aaron P
authors: AP
authors: Seitz
authors: Michael J
authors: MJ
authors: Edwards
authors: Heike
authors: H
authors: Grassmé
authors: Ildiko
authors: I
authors: Szabò
authors: Erich
authors: E
authors: Gulbins
mesh_terms: D000818:Animals; D016923:Cell Death; D002460:Cell Line; D002518:Ceramides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D019169:Jurkat Cells; D008099:Liver / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D011552:Pseudomonas Infections / Q000378:metabolism / Q000382:microbiology*; D011550:Pseudomonas aeruginosa / Q000378:metabolism*; D011710:Pyocyanine / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism
chemical_list: C508606:CXCL8 protein, human; D002518:Ceramides; D016209:Interleukin-8; D017382:Reactive Oxygen Species; D045304:Cytochromes c; D011710:Pyocyanine; D013108:Sphingomyelin Phosphodiesterase