The selective NLRP3 inflammasome inhibitor MCC950 alleviates cholestatic liver injury and fibrosis in mice

Qu, Junwen; Yuan, Zhiqing; Wang, Guiyang; Wang, Xiaopeng; Li, Kewei

doi:10.1016/j.intimp.2019.02.016

Cited by 75 publications

(49 citation statements)

References 37 publications

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“…Initial reports have also addressed possible targets for therapeutic interventions that may interfere with inflammasome activation. The intraperitoneal administration of MCC950, a specific small molecule inhibitor of NLRP3, resulted in the amelioration of liver injury, survival and fibrosis in BDL-treated mice, strongly supporting a possible therapeutic modulation of the inflammasome [97]. Previous studies have shown that Galectin-3, a lectin produced by macrophages, may activate the NLRP3 inflammasome in the liver and contribute to collagen deposition in a murine model of cholestasis [98].…”

Section: Inflammasome Activation In Cholestatic Liver Injurymentioning

confidence: 80%

Gut–Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology

Maroni

Ninfole

Pinto

et al. 2020

Cells

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The Nlrp3 inflammasome is a multiprotein complex activated by a number of bacterial products or danger signals and is involved in the regulation of inflammatory processes through caspase-1 activation. The Nlrp3 is expressed in immune cells but also in hepatocytes and cholangiocytes, where it appears to be involved in regulation of biliary damage, epithelial barrier integrity and development of fibrosis. Activation of the pathways of innate immunity is crucial in the pathophysiology of hepatobiliary diseases, given the strong link between the gut and the liver. The liver secretes bile acids, which influence the bacterial composition of the gut microbiota and, in turn, are heavily modified by microbial metabolism. Alterations of this balance, as for the development of dysbiosis, may deeply influence the composition of the bacterial products that reach the liver and are able to activate a number of intracellular pathways. This alteration may be particularly important in the pathogenesis of cholangiopathies and, in particular, of primary sclerosing cholangitis, given its strong association with inflammatory bowel disease. In the present review, we summarize current knowledge on the gut-liver axis in cholangiopathies and discuss the role of Nlrp3 inflammasome activation in cholestatic conditions.

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Section: Inflammasome Activation In Cholestatic Liver Injurymentioning

confidence: 80%

Gut–Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology

Maroni

Ninfole

Pinto

et al. 2020

Cells

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“…55 Interestingly, a selective NLRP3 chemical inhibitor attenuated liver fibrosis, suggesting that the reduced activity of the NLRP3 inflammasome might have beneficial effects in the treatment of liver injury. 56 Thus, blocking the upstream factors in the proinflammatory signaling pathways may open new therapeutic opportunities. Fig.…”

Section: Discussionmentioning

confidence: 99%

NLRP3 inflammasome blockade reduces adipose tissue inflammation and extracellular matrix remodeling

et al. 2019

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The NLRP3-IL-1β pathway plays an important role in adipose tissue (AT)-induced inflammation and the development of obesityassociated comorbidities. We aimed to determine the impact of NLRP3 on obesity and its associated metabolic alterations as well as its role in adipocyte inflammation and extracellular matrix (ECM) remodeling. Samples obtained from 98 subjects were used in a case−control study. The expression of different components of the inflammasome as well as their main effectors and inflammation-and ECM remodeling-related genes were analyzed. The impact of blocking NLRP3 using siRNA in lipopolysaccharide (LPS)-mediated inflammation and ECM remodeling signaling pathways was evaluated. We demonstrated that obesity (P < 0.01), obesity-associated T2D (P < 0.01) and NAFLD (P < 0.05) increased the expression of different components of the inflammasome as well as the expression and release of IL-1β and IL-18 in AT. We also found that obese patients with T2D exhibited increased (P < 0.05) hepatic gene expression levels of NLRP3, IL1B and IL18. We showed that NLRP3, but not NLRP1, is regulated by inflammation and hypoxia in visceral adipocytes. We revealed that the inhibition of NLRP3 in human visceral adipocytes significantly blocked (P < 0.01) LPS-induced inflammation by downregulating the mRNA levels of CCL2, IL1B, IL6, IL8, S100A8, S100A9, TLR4 and TNF as well as inhibiting (P < 0.01) the secretion of IL1-β into the culture medium. Furthermore, blocking NLRP3 attenuated (P < 0.01) the LPS-induced expression of important molecules involved in AT fibrosis (COL1A1, COL4A3, COL6A3 and MMP2). These novel findings provide evidence that blocking the expression of NLRP3 reduces AT inflammation with significant fibrosis attenuation.

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“…Without effective treatment, severe cholestasis may lead to hepatocellular impairment, liver fibrosis, or eventually cirrhosis, hepatic failure, and carcinoma. A growing body of evidence indicates that the NLRP3 inflammasome is significantly activated and plays an important role in cholestatic liver injury and fibrosis (Gong et al, 2016;Hao et al, 2017;Qu et al, 2019). Liver damage and fibrosis due to cholestasis can be alleviated by using NLRP3 inhibitors or by NLRP3 knockout in vivo (Ma et al, 2018;Yang et al, 2018;Qu et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…Bile duct ligation surgeries were performed as previous described (Qu et al, 2019) and sham operation group underwent the same procedure except for BDL and served as healthy controls. The low dose (LD; 80 µg/kg) of calcipotriol were referenced from a previous study and proved to be most effective in anti-fibrosis and liver protection in that in vivo experiment (Wahsh et al, 2016).…”

Section: Bile Duct Ligation (Bdl)-induced Cholestasismentioning

confidence: 99%

“…Moreover, activation of the NLRP3 pathway promotes hepatic stellate cell (HSC) activation, which is critical for the initiation and development of liver fibrosis (Watanabe et al, 2009;Inzaugarat et al, 2019). In a previous study, we proved that NLRP3 inhibition by MCC950, a selective NLRP3 inhibitor, can significantly alleviate liver injury and retard the development of fibrosis in bile-duct-ligation (BDL)-induced cholestasis in mice (Qu et al, 2019). Therefore, inhibiting activation of the NLRP3 inflammasome may be a potential therapeutic route for effectively treating cholestatic liver injury and fibrosis.…”

Section: Introductionmentioning

confidence: 97%

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Calcipotriol Inhibits NLRP3 Signal Through YAP1 Activation to Alleviate Cholestatic Liver Injury and Fibrosis

Wang

et al. 2020

Front. Pharmacol.

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Cholestasis is common in multiple clinical circumstances. The NOD-like receptor protein 3 (NLRP3) inflammasome pathway has been demonstrated to play an important role in liver injury and fibrosis induced by cholestasis. We previously proved that MCC950, a selective NLRP3 inhibitor, alleviates liver fibrosis and injury in experimental liver cholestasis induced by bile-duct ligation (BDL) in mice. Herein, we investigate the role of calcipotriol, a potent vitamin D receptor agonist, in experimental liver cholestasis, test its therapeutic efficacy, and explore its potential protective mechanism. C57BL/6 mice were made to undergo BDL or fed the 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet to establish two classic cholestatic models. Calcipotriol was administered intraperitoneally to these mice daily. Serum makers of liver damage and integrity, liver histological changes, levels of liver pro-fibrotic markers, bile acid synthetases and transporters were measured in vivo. The underlying mechanism by which calcipotriol alleviates cholestatic liver injury and fibrosis was further investigated. The results of the current study demonstrated that calcipotriol supplement significantly alleviate cholestatic liver injury and fibrosis. Moreover, calcipotriol supplement markedly inhibited NLRP3 inflammasome pathway activation to alleviate liver injury and fibrosis in vivo and inhibit hepatic stellate cell (HSC) activation in vitro. In addition, VDR agonist calcipotriol exert inhibitory effect on NLRP3 inflammasome activation through activating yes-associated protein 1 (YAP1). In conclusion, our findings proved that calcipotriol suppressed the NLRP3 signal by activating YAP1 to alleviate liver injury and retard fibrogenesis in cholestasis.

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The selective NLRP3 inflammasome inhibitor MCC950 alleviates cholestatic liver injury and fibrosis in mice

Cited by 75 publications

References 37 publications

Gut–Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology

Gut–Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology

NLRP3 inflammasome blockade reduces adipose tissue inflammation and extracellular matrix remodeling

Calcipotriol Inhibits NLRP3 Signal Through YAP1 Activation to Alleviate Cholestatic Liver Injury and Fibrosis

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