Galectin‐3 regulates inflammasome activation in cholestatic liver injury

Tian, Jianhui; Yang, Guoxiang; Chen, Huan‐Yuan; Hsu, Daniel K.; Tomilov, Alexey; Olson, Kristin; Dehnad, Ali; Fish, Sarah; Cortopassi, Gino A; Zhao, Keda; Liu, Fu‐Tong; Gershwin, M. Eric; Török, Natalie J.; Jiang, Joy X.

doi:10.1096/fj.201600392rr

Cited by 75 publications

(63 citation statements)

References 53 publications

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“…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]. Interestingly, treatment of mice with Davanat, a registered inhibitor of Galectin-3 that is currently being studied in clinical trials, determined a significant reduction in inflammasome activation and biliary damage in a model of autoimmune cholangitis [99].…”

Section: Inflammasome Activation In Cholestatic Liver Injurymentioning

confidence: 81%

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: 81%

Gut–Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology

Maroni

Ninfole

Pinto

et al. 2020

Cells

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“…In addition, Galectin-3 (Gal3), a macrophage produced lectin that was thought to be mediating activation of the inflammasome, was also increased on both the mRNA and the protein levels in these patients. Immunostaining of Gal-3 and NLFP3 were increased in liver sections but whether they were in macrophages or stellate cells was not clear (104). Thus, the role of inflammasomes in cholestatic liver injury remains elusive both in cholestataic animal models and in man and needs much further study.…”

Section: The Role Of the Inflammasome In Cholestatic Liver Injurymentioning

confidence: 99%

Mechanisms of bile acid mediated inflammation in the liver

Cai

Boyer

2017

Molecular Aspects of Medicine

207

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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“…In a secreted form, galectin‐3 elicits diverse biological responses that include adhesion of tumour cells to the vascular endothelium and activation of specific cell surface receptors such as Toll‐like receptor 4 . Exposure to galectin‐3 also exerts cytokine‐like regulatory actions and, indeed, promotes secretion of IL‐1 β in monocytes, macrophages and microglia . Interestingly, in our study, we found that exogenous galectin‐3 itself did not affect the levels of IL‐1 β , instead acting as an amplifier of the IL‐1 β ‐mediated inflammatory response.…”

Section: Discussionmentioning

confidence: 47%

Galectin‐3 is an amplifier of the interleukin‐1β‐mediated inflammatory response in corneal keratinocytes

et al. 2018

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Interleukin-1β (IL-1β) is a potent mediator of innate immunity commonly up-regulated in a broad spectrum of inflammatory diseases. When bound to its cell surface receptor, IL-1β initiates a signalling cascade that cooperatively induces the expression of canonical IL-1 target genes such as IL-8 and IL-6. Here, we present galectin-3 as a novel regulator of IL-1β responses in corneal keratinocytes. Using the SNAP-tag system and digitonin semi-permeabilization, we show that recombinant exogenous galectin-3 binds to the plasma membrane of keratinocytes and is internalized into cytoplasmic compartments. We find that exogenous galectin-3, but not a dominant negative inhibitor of galectin-3 polymerization lacking the N-terminal domain, exacerbates the response to IL-1β by stimulating the secretion of inflammatory cytokines. The activity of galectin-3 could be reduced by a novel d-galactopyranoside derivative targeting the conserved galactoside-binding site of galectins and did not involve interaction with IL-1 receptor 1 or the induction of endogenous IL-1β. Consistent with these observations, we demonstrate that small interfering RNA-mediated suppression of endogenous galectin-3 expression is sufficient to impair the IL-1β-induced secretion of IL-8 and IL-6 in a p38 mitogen-activated protein kinase-independent manner. Collectively, our findings provide a novel role for galectin-3 as an amplifier of IL-1β responses during epithelial inflammation through an as yet unidentified mechanism.

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Galectin‐3 regulates inflammasome activation in cholestatic liver injury

Cited by 75 publications

References 53 publications

Gut–Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology

Gut–Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology

Mechanisms of bile acid mediated inflammation in the liver

Galectin‐3 is an amplifier of the interleukin‐1β‐mediated inflammatory response in corneal keratinocytes

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