Archives

  • 2018-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • br Results br Discussion The inflammasome

    2021-11-24


    Results
    Discussion The inflammasome consists of the sensor molecule nucleotide oligomerization domain (NOD)-like receptors (NLRs), the adaptor protein ASC, and the tcs products molecule CASP1 (Guo et al., 2015). Among the different types of inflammasome, the NLRP3 inflammasome requires a priming step because the basal expression of NLRP3 is insufficient; its upregulation is thus essential for inflammasome activation (Guo et al., 2015, Szabo and Csak, 2012). NLRP3 activation is mediated by two major steps: the expression of inflammasome components (signal 1) and their functional activation (signal 2; Szabo and Csak, 2012). Here, we report a functional role for FXR in the regulation of the NLRP3 inflammasome in hepatocytes. Our analysis of the GEO database showed that FXR is downregulated in patients with hepatic necrosis, whereas NLRP3 is upregulated, revealing the existence of an inverse relationship between FXR and the NLRP3 inflammasome. This inverse relationship was confirmed in animal models of induced liver injury (via APAP or CCl4 treatment or the MCDHF diet), showing that FXR is downregulated with NLRP3 inflammasome activation in different liver disease conditions. Our results from Fxr KO mice and from their treatment with an FXR agonist revealed that FXR can suppress the NLRP3 inflammasome when it is activated by ER stress in hepatocytes. Consistently, the data also showed that FXR activation inhibits NLRP3 and TXNIP, as well as ER stress-induced IL-1β secretion from the NLRP3 inflammasome. The concept that FXR negatively regulates the NLRP3 inflammasome is in line with a recent report that FXR protects against cholestasis-associated sepsis through its interaction with NLRP3 and CASP1 in macrophages (Hao et al., 2017). Our findings advance our understanding of the inhibitory effect of FXR on inflammasome gene regulation in hepatocytes subjected to ER stress. Moreover, the finding that FXR is upregulated in NAFLD human samples in the absence of inflammasome activation indicates that pathological events can also adaptively stimulate FXR expression in the liver during disease progression. So this inhibitory effect of FXR on inflammasome gene regulation might vary depending on disease severity. For example, most NAFLD patients in our study had mild to moderate steatosis (i.e., grade 1 or 2), which might account for the lack of IL-1β increase, as previously reported (Csak et al., 2011). Consequently, FXR levels might be repressed in certain conditions or adaptively enhanced in others. Thus, FXR might be an attractive target to inhibit the priming and activation processes of inflammasome and inflammasome-mediated liver diseases. Hepatocytes make up 70%–85% of the liver mass, have high metabolic activity, and have an abundance of ER, allowing this cell type to serve as a major sensor responding to ER stress. The ER stress-activated NLRP3 inflammasome may lead to hepatocyte injury. Consistent with our results, FXR was shown to be decreased upon ER stress (Xiong et al., 2014), suggestive of a feedforward loop between FXR loss and ER stress. An important finding of our study is the identification of FXR as a hepatoprotective regulator against catastrophic ER stress; our findings show that FXR ligand treatment ameliorated ER stress-mediated hepatocyte death and liver injury. Because mitochondrial function is closely linked to ER stress and inflammasome activation (Gurung et al., 2015, Senft and Ronai, 2015), the beneficial effects of FXR on energy metabolism and mitochondrial function (Lee et al., 2012, Teodoro et al., 2011) may add value to the use of FXR as a therapeutic target for ER stress-associated liver diseases. NLRP3 gene regulation is poorly understood. Here, we identified PERK as a pathway for NLRP3 induction. In our siRNA experiments, we knocked down components of three canonical UPR pathways and revealed that PERK signaling is specifically involved in NLRP3 induction by ER stress in hepatocytes. In support of this, NLRP3 expression was enhanced by PERK overexpression, and IL-1β production was attenuated by Perk knockdown. In addition, our results show that FXR modulates PERK phosphorylation and subsequent CHOP expression. Our findings indicate that CHOP is a potential transcriptional factor that is necessary for NLRP3 expression downstream of PERK, and the ChIP assay results confirm that CHOP interacts with the NLRP3 gene. Of the three CHOP response elements located within the −2.2-kb promoter region of the human NLRP3 gene, the core sequences of CHOP-RE1 and CHOP-RE3 resemble CCAAT-enhancer binding protein-activating transcription factor (C/EBP-ATF) response elements (CAREs) (Kilberg et al., 2009, Teske et al., 2013). Additionally, the same CHOP-RE2 sequence regulated TRB3, another ER stress-inducible gene (Ohoka et al., 2005). CHOP promotes cell death signals through the regulation of pro-CASP1 (Lebeaupin et al., 2015). Therefore, the identified PERK-CHOP pathway seems to be critical for inflammasome-mediated hepatocyte death during the progression of liver diseases.