Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official. Federal government websites often end in . gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site. VSports app下载.

Https

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. V体育官网.

. 2021 Jun 13:27:101051.
doi: 10.1016/j.bbrep.2021.101051. eCollection 2021 Sep.

FXR/TGR5 mediates inflammasome activation and host resistance to bacterial infection

Ju-Hee Kang  1 , Minji Kim  1 , Mijung Yim  1
Affiliations

FXR/TGR5 mediates inflammasome activation and host resistance to bacterial infection

Ju-Hee Kang et al. Biochem Biophys Rep. .

Abstract

Bacterial infections are a major cause of chronic infections and mortality. Innate immune control is crucial for protection against bacterial pathogens. Bile acids facilitate intestinal absorption of lipid-soluble nutrients and modulate various metabolic pathways through the farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5) VSports手机版. Here, we identified a new role of FXR and TGR5 in promoting inflammasome activation during bacterial infection. Caspase-1/11 activation and release of cleaved interleukin (IL)-1β in FXR- and TGR5-deficient mouse bone marrow-derived macrophages upon Listeria monocytogenes or Escherichia coli infection was significantly reduced. In contrast, FXR- or TGR5-deficiency did not affect the transcription of caspase-1/11 and IL-1β. Inflammasome activation is critical for host immune defense against bacterial infections. Consistent with this, the deletion of FXR or TGR5 impaired effective clearance of L. monocytogenes or E. coli in vitro and in vivo, which was associated with greater mortality and bacterial burden than that of wild-type mice. Pretreatment with an FXR agonist decreased bacterial burden in vitro and increased survival in vivo. Thus, FXR and TGR5 promote inflammasome-mediated antimicrobial responses and may represent novel antibacterial therapeutic targets. .

Keywords: BMDM, bone marrow-derived macrophages; Bacterial infection; FXR; FXR, Farnesoid X receptor; Immune defense; Inflammasome; TGR5; TGR5, Takeda G-protein-coupled receptor. V体育安卓版.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
Macrophages lacking FXR display decreased levels of inflammasomes and IL-1β. Primary BMDMs were derived from wild-type (WT) or FXR−/− mice and were infected with L. monocytogenes (A, C, E and G) for 5 h, or E. coli for 16 h (B, D, F and H) at MOI 50. (A, B) Immunoblotting of cell lysates (Lys) and supernatants (Sup). (C, D) Graphs of the densitometry for immunoblots. (E, F) IL-1β level in the supernatant of BMDMs. (G, H) TNF-α level in the supernatant of BMDMs. Data represent three independent experiments (n = 3). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 significantly different from WT.
Fig. 2
Fig. 2
FXR deficiency results in an enhanced bacterial burden associated with increased mortality. (A, B) BMDMs were derived from WT or FXR−/− mice and infected with L. monocytogenes (A) for 5 h or E. coli (B) for 16 h at MOI 50. Quantification of bacterial burdens in BMDMs at indicated times post-infection (n = 3). (C, D) IL-1β serum levels in WT and FXR−/− mice infected with 1 × 105 CFU L. monocytogenes (C) or 2 × 109 CFU E. coli (D) at day 2 (L. monocytogenes) or 24 h (E. coli) post-infection (n = 3) (E, F) Bacterial burden in the liver or spleen at day 2 (L. monocytogenes) or 6 h (E. coli) post-infection. (G) Stained WT and FXR−/− livers 2 days after L. monocytogenes infection. Infiltration of inflammatory cells are indicated by arrowheads. H&E stain; × 100. (H, I) Percentage survival of WT and FXR−/− mice infected with 5 × 105 CFU L. monocytogenes (n = 16–22, H) or 5 × 109 CFU E. coli (n = 10–12, I). **p < 0.01, ***p < 0.001, ****p < 0.0001 significantly different from WT. Scale bar = 100 μm; veh: vehicle; LM: L. monocytogenes.
Fig. 3
Fig. 3
FXR agonists enhance mouse survival by improving bacterial clearance (A–C) Quantification of bacterial burden in BMDMs 2-h post-infection. Primary BMDMs were pretreated with fexaramine (5 μM), CDCA (50 μM), or 6-ECDCA (50 μM) before L. monocytogenes (A) or E. coli (B) infection (n = 3). Primary BMDMs from WT or NLRP3−/− mice were pretreated with 6-ECDCA (50 μM) before L. monocytogenes infection (n = 3) (C). (D, E) Percentage survival of mice infected with 5 × 105 CFU L. monocytogenes (n = 7–8, D) or 5 × 109 CFU E. coli (n = 6, E) and treated with 6-ECDCA. Mice were injected i.p. with 5 mg/kg/day 6-ECDCA or with vehicle daily for 6 days starting from 1 day before bacterial infection. (F, G) Bacterial burden of the liver or spleen in response to 6-ECDCA treatment. Bacterial burden was enumerated on day 2 (L. monocytogenes, F) or 6 h (E. coli, G) post-infection. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 significantly different from Veh. LM: L. monocytogenes, fexa: fexaramine, E: E. coli.
Fig. 4
Fig. 4
TGR5 deficiency is associated with decreased levels of inflammasomes and enhanced bacterial burden. (A, B) BMDMs were derived from WT or TGR5−/− mice and infected with L. monocytogenes (A) for 5 h or E. coli (B) for 16 h at MOI 50. Immunoblotting of cell lysates (Lys) and supernatants (Sup). (C, D) Graphs of the densitometry for immunoblots (n = 3). (E, F) The level of IL-1β in the supernatant of BMDMs (n = 3). (G, H) Serum levels of IL-1β in WT and TGR5−/− mice infected with 1 × 105 CFU L. monocytogenes (G) or 2 × 109 CFU E. coli (H) infection at day 2 (L. monocytogenes) or 24 h (E. coli) (n = 3). (I, J) Quantification of bacterial burden. The bacterial burden of the liver or spleen was enumerated on day 2 (L. monocytogenes, I) or 6 h (E. coli, J) post-infection. (K, L) Percentage survival of WT and TGR5−/− mice infected with 5 × 105 CFU L. monocytogenes (n = 15–19, K) or 5 × 109 CFU E. coli (n = 12–16, L). *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001 significantly different from WT.
See this image and copyright information in PMC

References

    1. Rivera A., Siracusa M.C., Yap G.S., Gause W.C. Innate cell communication kick starts pathogen specific immunity. Nat. Immunol. 2016;17:356–363. doi: 10.1038/ni.3375. - DOI - PMC - PubMed
    1. Cao X. Self-regulation and cross-regulation of pattern-recognition receptor signalling in health and disease. Nat. Rev. Immunol. 2016;16:35–50. doi: 10.1038/nri.2015.8. - "VSports在线直播" DOI - PubMed
    1. Sharma D., Kanneganti T.-D. The cell biology of inflammasomes: mechanisms of inflammasome activation and regulation. J. Cell Biol. 2016;213(6):617–629. doi: 10.1083/jcb.201602089. - DOI - PMC - PubMed
    1. Shin S., Brodsky I.E. The inflammasome: learning from bacterial evasion strategies. Semin. Immunol. 2015;27:102–110. doi: 10.1016/j.smim.2015.03.006. - DOI - PubMed
    1. Shimada K., Crother T.R., Karlin J. Caspase-1 dependent IL-1beta secretion is critical for host defense in a mouse model of Chlamydia pneumoniae lung infection. PloS One. 2011;6 doi: 10.1371/journal.pone.0021477. - DOI - PMC - PubMed

LinkOut - more resources