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

Abstract

BackgroundThe 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.ResultsRelease 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.ConclusionsIL-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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-014-0030-7) contains supplementary material, which is available to authorized users.

Intestinal epithelial NAIP/NLRC4 restricts systemic dissemination of the adapted pathogen Salmonella Typhimurium due to site-specific bacterial PAMP expression

“…Taken together, our data extend previous work, 10,11,37,39,42,44,45,47,49,50,76 highlight that in vivo studies of host-pathogen interactions are highly sensitive to the experimental conditions, and may be subject to confounding effects that limit reproducibility. The general approach presented here-a combination of littermate controlled infections, host cell typespecific gene knockouts, genetically tagged bacterial consortia, mathematical modeling and high-resolution imaging of the infected cells/organs-allowed us to decipher the impact of specific host responses in vivo.…”

“…NLRP3 and Caspase-11 are dispensable for control of S. Tm dissemination from the gut, even in the absence of NLRC4 The significance of the NLRP3 inflammasome and the noncanonical Caspase-11 inflammasome during oral S. Tm infection and their role in limiting pathogen levels at systemic sites are ambiguous. 11,37,39,43,49,50 To quantitatively assess the involvement of these inflammasomes, we infected Nlrp3 −/−67 and Casp11 −/−41 mice using the experimental setup described in Fig. 1.…”

“…Mathematical modeling suggests that this effect is due to a Caspase-1 mediated restriction of initial S. Tm migration to the spleen, rather than involvement in suppression of pathogen replication within this organ ( Fig. 4d, population structure, µ and 37,39,43,47,49,50,76 It should be noted that differences in the studied infection time points or distinct virulence factor expression patterns of the employed S. Tm strains may also account for disparate phenotypes. Nevertheless, in our iv infections, Caspase-1 mediated defense appears independent of NLRC4, NLRP3, or Caspase-11.…”

17β-Estradiol transcriptionally modulates Nlrp1 and Nlrp3 inflammasomes in gonadectomized rats with inflammation

“…Although inflammasomes are well known to participate in intracellular responses to pathogens and stress, their roles in the innate response caused by inflammation and in autoimmune diseases, metabolic disorders and cancer are receiving increasing attention [23][24][25][26] . The role of estrogens in inflammation has been widely studied, but there are few studies that have specifically addressed the biological effects of CFA in combination with estrogen to evaluate the transcriptional activation of the inflammasomes.…”

Salmonella Virulence Factor SsrAB Regulated Factor Modulates Inflammatory Responses by Enhancing the Activation of NF-κB Signaling Pathway

“…The histological inflammatory lesions were quantified and scored in a blinded manner as previously described (44). All of the animal experiments were conducted according to local animal care advisory committee guidelines.…”