Pathogenic Vibrio Activate NLRP3 Inflammasome via Cytotoxins and TLR/Nucleotide-Binding Oligomerization Domain-Mediated NF- B Signaling

Division of Bacterial Pathogenesis, Graduate School of Medicine, University of the Ryukyus, Okinawa.
The Journal of Immunology (Impact Factor: 4.92). 03/2010; 184(9):5287-97. DOI: 10.4049/jimmunol.0903536
Source: PubMed


Vibrio vulnificus and Vibrio cholerae are Gram-negative pathogens that cause serious infectious disease in humans. The beta form of pro-IL-1 is thought to be involved in inflammatory responses and disease development during infection with these pathogens, but the mechanism of beta form of pro-IL-1 production remains poorly defined. In this study, we demonstrate that infection of mouse macrophages with two pathogenic Vibrio triggers the activation of caspase-1 via the NLRP3 inflammasome. Activation of the NLRP3 inflammasome was mediated by hemolysins and multifunctional repeat-in-toxins produced by the pathogenic bacteria. NLRP3 activation in response to V. vulnificus infection required NF-kappaB activation, which was mediated via TLR signaling. V. cholerae-induced NLRP3 activation also required NF-kappaB activation but was independent of TLR stimulation. Studies with purified V. cholerae hemolysin revealed that toxin-stimulated NLRP3 activation was induced by TLR and nucleotide-binding oligomerization domain 1/2 ligand-mediated NF-kappaB activation. Our results identify the NLRP3 inflammasome as a sensor of Vibrio infections through the action of bacterial cytotoxins and differential activation of innate signaling pathways acting upstream of NF-kappaB.

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    • "The Gram-negative pathogens Vibrio vulnificus and V. cholera have been reported to trigger the activation of caspase-1 and IL-1β secretion in macrophages via NLRP3 inflammasome activation [31]. Salmonella typhimurium, a Gram-negative flagellated bacterium, induces the activation of the NLRC4/IPAF inflammasome [14,32]. "
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    • "Similarly, pneumolysin, produced by Streptococcus pneumoniae, or streptolysin O, produced by S. pyogenes, induces the NLRP3 inflammasome , and in vivo studies using NLRP3-deficient mice exhibited an impaired clearance of S. pneumoniae but not of S. pyogenes (Harder et al., 2009; McNeela et al., 2010). Cytotoxins, including aerolysins secreted by A. hydrophila or A. veronii, and haemolysins and multifunctional repeat-in-toxins, secreted by Vibrio vulnificus or V. cholerae, also lead to the activation of the NLRP3 inflammasome through the induction of potassium efflux (McCoy et al., 2010a,b; Toma et al., 2010). Staphylococcus aureus triggers NLRP3 activation mediated by one of several toxins (Craven et al., 2009). "
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