Limited role for ASC and NLRP3 during in vivo Salmonella Typhimurium infection

BMC Immunol. 2014 Aug 13;15:30. doi: 10.1186/s12865-014-0030-7.

Abstract

Background: The inflammasome is an intracellular protein complex triggered by exposure to intracellular pathogens, its components or other endogenous proteins. It leads to the activation of and subsequent release of proinflammatory cytokines such as IL-1β and IL-18. S. Typhimurium is a Gram-negative intracellular bacterium, which is known to trigger inflammasome assembly via recognition by the cytosolic receptors, NLRP3 and NLRC4 (which act via the adaptor protein, ASC) to induce cell death and cytokine release. We sought to characterize the role of ASC and NLRP3 in two different murine models (typhoid and colitis) of systemic Salmonella infection.

Results: Release of the inflammasome cytokine IL-18 was hampered in Asc-/- but not Nlrp3-/- mice (background C57BL/6) during S. Typhimurium infection. Unexpectedly, neither ASC nor NLRP3 played a significant role in host defense against S. Typhimurium infection, as reflected by equal bacterial counts in WT, Asc-/- and Nlrp3-/- mice at all time points, in both the typhoid and colitis models. Proinflammatory cytokine levels (TNF-α, IL-6) and the extent of hepatic and splenic pathology did not differ between groups in the typhoid model. In the colitis model small differences were seen with regard to splenic and hepatic inflammation, although this was IL-18 independent.

Conclusions: IL-18 release was reduced in Asc-/- but not Nlrp3-/- mice during S. Typhimurium infection. Despite this reduction, bacterial counts, cytokine levels and histological inflammation did not differ between wild-type and knockout mice in either model. Our results reveal a limited role for ASC and NLRP3 during in vivo S. Typhimurium infection despite its role in cytokine maturation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / deficiency
  • Apoptosis Regulatory Proteins / metabolism*
  • Biomarkers / metabolism
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / metabolism*
  • Colitis / immunology
  • Colitis / microbiology
  • Colitis / pathology
  • Colony Count, Microbial
  • Cytokines / metabolism
  • Disease Models, Animal
  • Disease Susceptibility
  • Host-Pathogen Interactions / immunology
  • Inflammasomes / metabolism
  • Inflammation / pathology
  • Interleukin-18 / metabolism
  • Intestines / microbiology
  • Intestines / pathology
  • Liver / pathology
  • Mice, Inbred C57BL
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Organ Specificity
  • Salmonella Infections, Animal / immunology*
  • Salmonella Infections, Animal / microbiology
  • Salmonella Infections, Animal / pathology
  • Salmonella typhimurium / immunology*
  • Typhoid Fever / immunology
  • Typhoid Fever / pathology

Substances

  • Apoptosis Regulatory Proteins
  • Biomarkers
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytokines
  • Inflammasomes
  • Interleukin-18
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Pycard protein, mouse