title: Aggregatibacter actinomycetemcomitans cytolethal distending toxin activates the NLRP3 inflammasome in human macrophages, leading to the release of proinflammatory cytokines.
abstract: The cytolethal distending toxin (Cdt) is produced from a number of bacteria capable of causing infection and inflammatory disease. Our previous studies with Actinobacillus actinomycetemcomitans Cdt demonstrate not only that the active toxin subunit functions as a phosphatidylinositol-3,4,5-triphosphate (PIP3) phosphatase but also that macrophages exposed to the toxin were stimulated to produce proinflammatory cytokines. We now demonstrate that the Cdt-induced proinflammatory response involves the activation of the NLRP3 inflammasome. Specific inhibitors and short hairpin RNA (shRNA) were employed to demonstrate requirements for NLRP3 and ASC as well as caspase-1. Furthermore, Cdt-mediated inflammasome activation is dependent upon upstream signals, including reactive oxygen species (ROS) generation and Cdt-induced increases in extracellular ATP levels. Increases in extracellular ATP levels contribute to the activation of the P2X7 purinergic receptor, leading to K+ efflux. The relationship between the abilities of the active toxin subunit CdtB to function as a lipid phosphatase, activate the NLRP3 inflammasome, and induce a proinflammatory cytokine response is discussed. These studies provide new insight into the virulence potential of Cdt in mediating the pathogenesis of disease caused by Cdt-producing organisms such as Aggregatibacter actinomycetemcomitans.
authors: Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA shenker@upenn.edu.
authors: Bruce J
authors: BJ
authors: Shenker
authors: School of Natural Sciences, University of California, Merced, California, USA.
authors: David M
authors: DM
authors: Ojcius
authors: Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.
authors: Lisa P
authors: LP
authors: Walker
authors: Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.
authors: Ali
authors: A
authors: Zekavat
authors: Department of Pathology, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.
authors: Monika Damek
authors: MD
authors: Scuron
authors: Department of Biochemistry, University of Pennsylvania School of Dental Medicine, Philadelphia, Pennsylvania, USA.
authors: Kathleen
authors: K
authors: Boesze-Battaglia
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001427:Bacterial Toxins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002352:Carrier Proteins / Q000276:immunology*; D020170:Caspase 1 / Q000276:immunology; D045744:Cell Line, Tumor; D016207:Cytokines / Q000378:metabolism*; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D058847:Inflammasomes / Q000276:immunology*; D007249:Inflammation / Q000276:immunology / Q000382:microbiology; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000276:immunology / Q000378:metabolism; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D001427:Bacterial Toxins; D002352:Carrier Proteins; D016207:Cytokines; C508585:IL1B protein, human; C508600:IL6 protein, human; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D015850:Interleukin-6; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D058486:Receptors, Purinergic P2X7; D014409:Tumor Necrosis Factor-alpha; C447141:cytolethal distending toxin, Actinobacillus actinomycetemcomitans; D000255:Adenosine Triphosphate; C096024:phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase; D010744:Phosphoric Monoester Hydrolases; D020170:Caspase 1; D011188:Potassium
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