Siglec-9 transduces apoptotic and nonapoptotic death signals into neutrophils depending on the proinflammatory cytokine environment.
We report about new apoptotic and non-apoptotic death pathways in neutrophils that are initiated via the surface molecule sialic acid-binding immunoglobulin-like lectin (Siglec)-9. In normal neutrophils, Siglec-9 ligation induced apoptosis. Inflammatory neutrophils obtained from patients with acute septic shock or rheumatoid arthritis demonstrated increased Siglec-9, but normal Fas receptor-mediated cytotoxic responses when compared with normal blood neutrophils. The increased Siglec-9-mediated death was mimicked in vitro by short-term preincubation of normal neutrophils with proinflammatory cytokines, such as granulocyte/macrophage colony-stimulating factor (GM-CSF), interferon-alpha (IFN-alpha), and IFN-gamma, and was demonstrated to be caspase independent. Experiments using scavengers of reactive oxygen species (ROS) or neutrophils unable to generate ROS indicated that both Siglec-9-mediated caspase-dependent and caspase-independent forms of neutrophil death depend on ROS. Interestingly, the caspase-independent form of neutrophil death was characterized by cytoplasmic vacuolization and several other nonapoptotic morphologic features, which were also seen in neutrophils present in joint fluids from rheumatoid arthritis patients. Taken together, these data suggest that apoptotic (ROS- and caspase-dependent) and nonapoptotic (ROS-dependent) death pathways are initiated in neutrophils via Siglec-9. The new insights have important implications for the pathogenesis, diagnosis, and treatment of inflammatory diseases such as sepsis and rheumatoid arthritis.
von Gunten
Stephan
S
Department of Pharmacology, University of Bern, Friedbühlstrasse 49, CH-3010 Bern, Switzerland.
Yousefi
Shida
S
Seitz
Michael
M
Jakob
Stephan M
SM
Schaffner
Thomas
T
Seger
Reinhard
R
Takala
Jukka
J
Villiger
Peter M
PM
Simon
Hans-Uwe
HU
D015703:Antigens, CD / Q000502:physiology*; D017209:Apoptosis; D001172:Arthritis, Rheumatoid / Q000473:pathology; D016022:Case-Control Studies; D020169:Caspases / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D037102:Lectins / Q000502:physiology*; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012772:Shock, Septic / Q000473:pathology; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D015398:Signal Transduction
D015703:Antigens, CD; D016207:Cytokines; D037102:Lectins; D017382:Reactive Oxygen Species; C412227:SIGLEC9 protein, human; D063265:Sialic Acid Binding Immunoglobulin-like Lectins; D020169:Caspases