Journal
JOURNAL OF IMMUNOLOGY
Volume 184, Issue 9, Pages 5287-5297Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.0903536
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Funding
- Japanese Ministry of Education, Culture, Sports, and Technology in Japan
- Takeda Science Foundation
- Uehara Memorial Foundation
- Ohyama Health Foundation
- National Institutes of Health [AI063331, AR051790]
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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-kappa B activation, which was mediated via TLR signaling. V. cholerae-induced NLRP3 activation also required NF-kappa B 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-kappa B 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-kappa B. The Journal of Immunology, 2010, 184: 5287-5297.
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