Abstract
Intracellular pathogens and endogenous danger signals in the cytosol engage NOD-like receptors (NLRs), which assemble inflammasome complexes to activate caspase-1 and promote the release of proinflammatory cytokines IL-1beta and IL-18. However, the NLRs that respond to microbial pathogens in vivo are poorly defined. We show that the NLRs NLRP3 and NLRC4 both activate caspase-1 in response to Salmonella typhimurium. Responding to distinct bacterial triggers, NLRP3 and NLRC4 recruited ASC and caspase-1 into a single cytoplasmic focus, which served as the site of pro-IL-1beta processing. Consistent with an important role for both NLRP3 and NLRC4 in innate immune defense against S. typhimurium, mice lacking both NLRs were markedly more susceptible to infection. These results reveal unexpected redundancy among NLRs in host defense against intracellular pathogens in vivo.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animal Structures / microbiology
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Animals
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Apoptosis Regulatory Proteins / genetics*
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Bacterial Proteins / genetics
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Blood / microbiology
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CARD Signaling Adaptor Proteins
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Calcium-Binding Proteins / genetics*
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Carrier Proteins / genetics*
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Caspase 1 / genetics
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Caspase 1 / metabolism
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Caspase Inhibitors
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Cysteine Proteinase Inhibitors / pharmacology
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Cytoplasmic Structures / drug effects
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Cytoplasmic Structures / genetics
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Cytoplasmic Structures / immunology
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Cytoplasmic Structures / metabolism
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism
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Flagellin / genetics
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Immunity, Innate / physiology*
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Interleukin-1 / metabolism
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Interleukin-18 / blood
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Interleukin-18 / metabolism
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Interleukin-1beta / blood
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Interleukin-1beta / metabolism
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Macrophages / metabolism
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Macrophages / microbiology
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Membrane Proteins / genetics
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Mice
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Mice, Inbred Strains
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Mice, Knockout
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Models, Immunological
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NLR Family, Pyrin Domain-Containing 3 Protein
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Protein Precursors / metabolism
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Protein Transport / genetics
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Protein Transport / immunology
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Salmonella Infections / immunology*
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Salmonella Infections / microbiology
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Salmonella typhimurium / genetics
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Salmonella typhimurium / immunology
Substances
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Apoptosis Regulatory Proteins
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Bacterial Proteins
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CARD Signaling Adaptor Proteins
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Calcium-Binding Proteins
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Carrier Proteins
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Caspase Inhibitors
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Cysteine Proteinase Inhibitors
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Cytoskeletal Proteins
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Interleukin-1
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Interleukin-18
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Interleukin-1beta
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Ipaf protein, mouse
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Membrane Proteins
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Protein Precursors
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Pycard protein, mouse
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SPI-2 protein, Salmonella
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Spi1 protein, Salmonella
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interleukin 1 precursor
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Flagellin
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Caspase 1