Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome

Guo, Chao; Xie, Shujun; Chi, Zhexu; Zhang, Jinhua; Liu, Yangyang; Zhang, Li; Zheng, Mingzhu; Zhang, Xue; Xia, Dajing; Ke, Yuehai; Lu, Linrong; Wang, Di

doi:10.1016/j.immuni.2016.09.008

Cited by 572 publications

(503 citation statements)

References 51 publications

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“…A very recent report exhibited by Guo and colleagues (44) showed that opposite to our findings, bile acids conveyed an inhibitory effect on NLRP3 inflammasome activation. In this report, they demonstrated that bile acids inhibited NLRP3 inflammasome activation via the TGR5-cAMP-PKA axis, whereas our data showed that DCA triggered NLRP3 inflammasome activation through S1PR2-cathepsin B pathway, one possible explanation of the discrepancy is that bile acids may have dual regulatory effect on inflammasome activation by different mechanisms.…”

Section: Discussioncontrasting

confidence: 99%

Deoxycholic Acid Triggers NLRP3 Inflammasome Activation and Aggravates DSS-Induced Colitis in Mice

et al. 2016

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A westernized high-fat diet (HFD) is associated with the development of inflammatory bowel disease (IBD). High-level fecal deoxycholic acid (DCA) caused by HFD contributes to the colonic inflammatory injury of IBD; however, the mechanism concerning the initiation of inflammatory response by DCA remains unclear. In this study, we sought to investigate the role and mechanism of DCA in the induction of inflammation via promoting NLRP3 inflammasome activation. Here, we, for the first time, showed that DCA dose-dependently induced NLRP3 inflammasome activation and highly pro-inflammatory cytokine-IL-1β production in macrophages. Mechanistically, DCA-triggered NLRP3 inflammasome activation by promoting cathepsin B release at least partially through sphingosine-1-phosphate receptor 2. Colorectal instillation of DCA significantly increased mature IL-1β level in colonic tissue and exacerbated DSS-induced colitis, while in vivo blockage of NLRP3 inflammasome or macrophage depletion dramatically reduced the mature IL-1β production and ameliorated the aggravated inflammatory injury imposed by DCA. Thus, our findings show that high-level fecal DCA may serve as an endogenous danger signal to activate NLRP3 inflammasome and contribute to HFD-related colonic inflammation. NLRP3 inflammasome may represent a new potential therapeutical target for treatment of IBD.

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Section: Discussioncontrasting

confidence: 99%

Deoxycholic Acid Triggers NLRP3 Inflammasome Activation and Aggravates DSS-Induced Colitis in Mice

et al. 2016

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“…TLCA or INT-777 treatment of mice subjected to LPS-induced sepsis or alum induced peritoneal inflammation significantly reduced IL-1β and IL-18 in Nlrp3 wild type mice but had no effect in Nlrp3 −/− mice. These findings suggest that bile acids place significant constraints on NLRP3 inflammasome -related inflammation (101), a finding supported by several earlier studies (90, 102). Opposite effects have been reported with chenodeoxycholic acid, which has been shown to activate the NLRP3 inflammasome in isolated macrophages as well as Kupffer cells initially sensitized to LPS(103).…”

Section: The Role Of the Inflammasome In Cholestatic Liver Injurysupporting

confidence: 84%

Mechanisms of bile acid mediated inflammation in the liver

Cai

Boyer

2017

Molecular Aspects of Medicine

194

120

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Bile acids are synthesized in the liver and are the major component in bile. Impaired bile flow leads to cholestasis that is characterized by elevated levels of bile acid in the liver and serum, followed by hepatocyte and biliary injury. Although the causes of cholestasis have been extensively studied, the molecular mechanisms as to how bile acids initiate liver injury remain controversial. In this chapter, we summarize recent advances in the pathogenesis of bile acid induced liver injury. These include bile acid signaling pathways in hepatocytes as well as the response of cholangiocytes and innate immune cells in the liver in both patients with cholestasis and cholestatic animal models. We focus on how bile acids trigger the production of molecular mediators of neutrophil recruitment and the role of the inflammatory response in this pathological process. These advances point to a number of novel targets where drugs might be judged to be effective therapies for cholestatic liver injury.

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“…Phosphorylation of protein kinase A (PKA) was reported to be a negative regulator of NLRP inflammasomes 51) . Transmembrane G protein-coupled receptor 5 (TGR5) bile acid receptor-induced PKA activation leads to the ubiquitination of NLRP3, which is associated with the PKA-induced NLRP3 phosphorylation (Ser 291).…”

Section: Nlrp3 Inflammasome In Atherosclerosismentioning

confidence: 99%

Role of NLRP3 Inflammasomes in Atherosclerosis

Karasawa

Takahashi

2017

J Atheroscler Thromb

229

162

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Inflammation with macrophage infiltration is a key feature of atherosclerosis. Although the mechanisms had been unclear, emerging evidence unveiled that NLRP3 inflammasomes, which regulate caspase-1 activation and subsequent processing of pro-IL-1β, trigger vascular wall inflammatory responses and lead to progression of atherosclerosis. NLRP3 inflammasomes are activated by various danger signals, such as cholesterol crystals, calcium phosphate crystals, and oxidized low-density lipoprotein in macrophages, to initiate inflammatory responses in the atherosclerotic lesion. Recent studies have further clarified the regulatory mechanisms and the potential therapeutic agents that target NLRP3 inflammasomes. In this study, we reviewed the present state of knowledge on the role of NLRP3 inflammasomes in the pathogenesis of atherosclerosis and discussed the therapeutic approaches that target NLRP3 inflammasomes.

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Bile Acids Control Inflammation and Metabolic Disorder through Inhibition of NLRP3 Inflammasome

Cited by 572 publications

References 51 publications

Deoxycholic Acid Triggers NLRP3 Inflammasome Activation and Aggravates DSS-Induced Colitis in Mice

Deoxycholic Acid Triggers NLRP3 Inflammasome Activation and Aggravates DSS-Induced Colitis in Mice

Mechanisms of bile acid mediated inflammation in the liver

Role of NLRP3 Inflammasomes in Atherosclerosis

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