Abstract
Citrobacter rodentium is an enteric bacterial pathogen of the mouse intestinal tract that triggers inflammatory responses resembling those of humans infected with enteropathogenic and enterohemorrhagic Escherichia coli. Inflammasome signaling is emerging as a central regulator of inflammatory and host responses to several pathogens, but the in vivo role of inflammasome signaling in host defense against C. rodentium has not been characterized. Here, we show that mice lacking the inflammasome components Nlrp3, Nlrc4, and caspase-1 were hypersusceptible to C. rodentium-induced gastrointestinal inflammation. This was due to defective interleukin (IL)-1β and IL-18 production given that il-1β(-/-) and il-18(-/-) mice also suffered from increased bacterial burdens and exacerbated histopathology. C. rodentium specifically activated the Nlrp3 inflammasome in in vitro-infected macrophages independently of a functional bacterial type III secretion system. Thus, production of IL-1β and IL-18 downstream of the Nlrp3 and Nlrc4 inflammasomes plays a critical role in host defense against enteric infections caused by C. rodentium.
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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Animals
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / immunology
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Apoptosis Regulatory Proteins / metabolism
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Bacterial Secretion Systems / genetics
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Bacterial Secretion Systems / immunology
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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / immunology
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Calcium-Binding Proteins / metabolism
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Carrier Proteins / genetics
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Carrier Proteins / immunology
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Carrier Proteins / metabolism
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Caspase 1 / genetics
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Caspase 1 / immunology
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Caspase 1 / metabolism
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Citrobacter rodentium / genetics
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Citrobacter rodentium / immunology*
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Citrobacter rodentium / metabolism
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Enterobacteriaceae Infections / genetics
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Enterobacteriaceae Infections / immunology*
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Enterobacteriaceae Infections / metabolism
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Enterobacteriaceae Infections / pathology
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Inflammasomes / genetics
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Inflammasomes / immunology*
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Inflammasomes / metabolism
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Interleukin-18 / genetics
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Interleukin-18 / immunology
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Interleukin-18 / metabolism
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Interleukin-1beta / genetics
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Interleukin-1beta / immunology
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Interleukin-1beta / metabolism
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Macrophages / immunology*
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Macrophages / metabolism
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Macrophages / microbiology
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Mice
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Mice, Knockout
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NLR Family, Pyrin Domain-Containing 3 Protein
Substances
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Apoptosis Regulatory Proteins
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Bacterial Secretion Systems
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Calcium-Binding Proteins
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Carrier Proteins
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Inflammasomes
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Interleukin-18
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Interleukin-1beta
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Ipaf protein, mouse
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Caspase 1