Abstract
Intestinal phagocytes transport oral antigens and promote immune tolerance, but their role in innate immune responses remains unclear. Here we found that intestinal phagocytes were anergic to ligands for Toll-like receptors (TLRs) or commensals but constitutively expressed the precursor to interleukin 1β (pro-IL-1β). After infection with pathogenic Salmonella or Pseudomonas, intestinal phagocytes produced mature IL-1β through the NLRC4 inflammasome but did not produce tumor necrosis factor (TNF) or IL-6. BALB/c mice deficient in NLRC4 or the IL-1 receptor were highly susceptible to orogastric but not intraperitoneal infection with Salmonella. That enhanced lethality was preceded by impaired expression of endothelial adhesion molecules, lower neutrophil recruitment and poor intestinal pathogen clearance. Thus, NLRC4-dependent production of IL-1β by intestinal phagocytes represents a specific response that discriminates pathogenic bacteria from commensal bacteria and contributes to host defense in the intestine.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
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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Calcium-Binding Proteins / genetics
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Calcium-Binding Proteins / immunology*
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Caspase 1 / metabolism
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Clonal Anergy*
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Flagellin / immunology
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Host-Pathogen Interactions / immunology*
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Humans
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Inflammasomes / immunology
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Inflammasomes / metabolism
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Interleukin-1beta / metabolism*
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Interleukin-6 / biosynthesis
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Interleukin-6 / immunology
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Intestines / immunology*
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Intestines / microbiology*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Monocytes / immunology
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Monocytes / metabolism
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Neutrophil Infiltration / genetics
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Neutrophil Infiltration / immunology
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Neutrophils / immunology
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Neutrophils / pathology
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Phagocytes / immunology*
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Phagocytes / microbiology
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Pseudomonas / immunology
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Pseudomonas Infections / immunology
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Receptors, Interleukin-1 / genetics
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Receptors, Interleukin-1 / immunology
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Salmonella / genetics
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Salmonella / immunology
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Salmonella Infections / genetics
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Salmonella Infections / immunology
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Signal Transduction / genetics
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Signal Transduction / immunology
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Toll-Like Receptors / immunology
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Toll-Like Receptors / metabolism
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Tumor Necrosis Factor-alpha / biosynthesis
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Tumor Necrosis Factor-alpha / immunology
Substances
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Apoptosis Regulatory Proteins
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Calcium-Binding Proteins
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Inflammasomes
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Interleukin-1beta
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Interleukin-6
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Ipaf protein, mouse
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Receptors, Interleukin-1
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Toll-Like Receptors
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Tumor Necrosis Factor-alpha
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Flagellin
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Caspase 1