Neutrophil Necroptosis Is Triggered by Ligation of Adhesion Molecules following GM-CSF Priming.
Apoptosis is the most common form of neutrophil death under both physiological and inflammatory conditions. However, forms of nonapoptotic neutrophil death have also been observed. In the current study, we report that human neutrophils undergo necroptosis after exposure to GM-CSF followed by the ligation of adhesion receptors such as CD44, CD11b, CD18, or CD15. Using a pharmacological approach, we demonstrate the presence of a receptor-interacting protein kinase-3 (RIPK3)-a mixed lineage kinase-like (MLKL) signaling pathway in neutrophils which, following these treatments, first activates p38 MAPK and PI3K, that finally leads to the production of high levels of reactive oxygen species (ROS). All these steps are required for necroptosis to occur. Moreover, we show that MLKL undergoes phosphorylation in neutrophils in vivo under inflammatory conditions. This newly identified necrosis pathway in neutrophils would imply that targeting adhesion molecules could be beneficial for preventing exacerbation of disease in the neutrophilic inflammatory response.
Institute of Pharmacology, University of Bern, CH-3010 Bern, Switzerland.
Xiaoliang
0000-0002-6021-6116
X
Wang
Institute of Pharmacology, University of Bern, CH-3010 Bern, Switzerland.
Zhaoyue
Z
He
Institute of Pharmacology, University of Bern, CH-3010 Bern, Switzerland.
He
H
Liu
Institute of Pharmacology, University of Bern, CH-3010 Bern, Switzerland.
Shida
0000-0002-9855-4305
S
Yousefi
Institute of Pharmacology, University of Bern, CH-3010 Bern, Switzerland hus@pki.unibe.ch.
Hans-Uwe
0000-0002-9404-7736
HU
Simon
D039481:CD11b Antigen / Q000378:metabolism; D018821:CD18 Antigens / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007249:Inflammation / Q000517:prevention & control; D016256:Lewis X Antigen / Q000378:metabolism; D009336:Necrosis; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D016897:Respiratory Burst; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D039481:CD11b Antigen; D018821:CD18 Antigens; C497483:CD44 protein, human; D015815:Cell Adhesion Molecules; D018960:Hyaluronan Receptors; C509295:ITGAM protein, human; D016256:Lewis X Antigen; D017382:Reactive Oxygen Species; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; C119705:RIPK3 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D048051:p38 Mitogen-Activated Protein Kinases