Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Bacterial Toxins / pharmacology*
-
Bone Marrow Cells / immunology
-
Bone Marrow Cells / microbiology
-
Bone Marrow Cells / pathology
-
Carrier Proteins / genetics
-
Carrier Proteins / metabolism*
-
Carrier Proteins / physiology
-
Caspase 1 / metabolism
-
Immunity, Innate / genetics
-
Inflammation / enzymology
-
Inflammation / immunology
-
Inflammation / microbiology
-
Interleukin-1beta / metabolism
-
Ligands
-
Macrophages / immunology
-
Macrophages / microbiology
-
Macrophages / pathology
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
NF-kappa B / physiology*
-
NLR Family, Pyrin Domain-Containing 3 Protein
-
Nod1 Signaling Adaptor Protein / metabolism
-
Nod1 Signaling Adaptor Protein / physiology*
-
Nod2 Signaling Adaptor Protein / metabolism
-
Nod2 Signaling Adaptor Protein / physiology*
-
Signal Transduction / genetics
-
Signal Transduction / immunology*
-
Toll-Like Receptors / physiology*
-
Vibrio cholerae / immunology
-
Vibrio cholerae / pathogenicity*
-
Vibrio vulnificus / immunology
-
Vibrio vulnificus / pathogenicity*
Substances
-
Bacterial Toxins
-
Carrier Proteins
-
Interleukin-1beta
-
Ligands
-
NF-kappa B
-
NLR Family, Pyrin Domain-Containing 3 Protein
-
Nlrp3 protein, mouse
-
Nod1 Signaling Adaptor Protein
-
Nod1 protein, mouse
-
Nod2 Signaling Adaptor Protein
-
Nod2 protein, mouse
-
Toll-Like Receptors
-
Caspase 1