Abstract
A flagellin-independent caspase-1 activation pathway that does not require NAIP5 or NRLC4 is induced by the intracellular pathogen Legionella pneumophila. Here we demonstrate that this pathway requires caspase-11. Treatment of macrophages with LPS up-regulated the host components required for this caspase-11 activation pathway. Activation by Legionella differed from caspase-11 activation using previously described agonists in that Legionella caspase-11 activation was rapid and required bacteria with a functional type IV secretion system called Dot/Icm. Legionella activation of caspase-11 induced pyroptosis by a mechanism independent of the NAIP/NLRC4 and caspase-1 axis. Legionella activation of caspase-11 stimulated activation of caspase-1 through NLRP3 and ASC. Induction of caspase-11-dependent responses occurred in macrophages deficient in the adapter proteins TRIF or MyD88 but not in macrophages deficient in both signaling factors. Although caspase-11 was produced in macrophages deficient in the type-I IFN receptor, there was a severe defect in caspase-11-dependent pyroptosis in these cells. These data indicate that macrophages respond to microbial signatures to produce proteins that mediate a capsase-11 response and that the caspase-11 system provides an alternative pathway for rapid detection of an intracellular pathogen capable of evading the canonical caspase-1 activation system that responds to bacterial flagellin.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Adaptor Proteins, Vesicular Transport / genetics
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Adaptor Proteins, Vesicular Transport / metabolism
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Animals
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Apoptosis*
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Bone Marrow Cells / metabolism
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Bone Marrow Cells / microbiology
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CARD Signaling Adaptor Proteins
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / metabolism
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Caspase 1 / genetics
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Caspase 1 / metabolism
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Caspases / genetics
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Caspases / metabolism*
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Caspases, Initiator
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Cells, Cultured
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Cytokines / metabolism
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism
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Enzyme Activation
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Flagellin / genetics
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Flagellin / metabolism*
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Host-Pathogen Interactions
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Immunoblotting
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Legionella pneumophila / genetics
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Legionella pneumophila / metabolism*
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Legionella pneumophila / physiology
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Macrophages / cytology
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Macrophages / metabolism*
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Macrophages / microbiology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mutation
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Myeloid Differentiation Factor 88 / genetics
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Myeloid Differentiation Factor 88 / metabolism
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NLR Family, Pyrin Domain-Containing 3 Protein
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Necrosis
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Receptor, Interferon alpha-beta / genetics
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Receptor, Interferon alpha-beta / metabolism
Substances
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Adaptor Proteins, Vesicular Transport
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Apoptosis Regulatory 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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Cytokines
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Cytoskeletal Proteins
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Ifnar1 protein, mouse
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Ipaf protein, mouse
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Myd88 protein, mouse
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Myeloid Differentiation Factor 88
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Pycard protein, mouse
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TICAM-1 protein, mouse
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Flagellin
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Receptor, Interferon alpha-beta
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Casp4 protein, mouse
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Caspases
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Caspases, Initiator
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Caspase 1