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: Bruce J Shenker, David M Ojcius, Lisa P Walker, Ali Zekavat, Monika Damek Scuron, Kathleen Boesze-Battaglia
• Journal: Infection and immunity (Infect Immun) Vol. 83 Issue 4 Pg. 1487-96 (Apr 2015) ISSN: 1098-5522 [Electronic] United States
• PMID: 25644004 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Chemical References

• Bacterial Toxins
• Carrier Proteins
• Cytokines
• IL1B protein, human
• IL6 protein, human
• Inflammasomes
• Interleukin-18
• Interleukin-1beta
• Interleukin-6
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human
• RNA, Small Interfering
• Reactive Oxygen Species
• Receptors, Purinergic P2X7
• Tumor Necrosis Factor-alpha
• cytolethal distending toxin, Actinobacillus actinomycetemcomitans
• Adenosine Triphosphate
• phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase
• Phosphoric Monoester Hydrolases
• Caspase 1
• Potassium

Topics

• Adenosine Triphosphate (metabolism)
• Bacterial Toxins (genetics, immunology, metabolism)
• Carrier Proteins (immunology)
• Caspase 1 (immunology)
• Cell Line, Tumor
• Cytokines (metabolism)
• Enzyme Activation (immunology)
• Humans
• Inflammasomes (immunology)
• Inflammation (immunology, microbiology)
• Interleukin-18 (immunology, metabolism)
• Interleukin-1beta (immunology, metabolism)
• Interleukin-6 (immunology, metabolism)
• Macrophages (immunology)
• NLR Family, Pyrin Domain-Containing 3 Protein
• Phosphoric Monoester Hydrolases (metabolism)
• Potassium (metabolism)
• RNA Interference
• RNA, Small Interfering (genetics)
• Reactive Oxygen Species (metabolism)
• Receptors, Purinergic P2X7 (metabolism)
• Tumor Necrosis Factor-alpha (immunology, metabolism)