Gut-Liver Axis and Inflammasome Activation in Cholangiocyte Pathophysiology

Abstract

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.

Keywords: NLRP3; cholangiocyte; gut–liver axis; inflammasome.

Figure 1

Two-step model of nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing-3 (NLRP3) inflammasome activation. In the first step, pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) activate the nuclear factor (NF)-κB pathway through the stimulation of receptors such as toll-like receptor (TLR)4, nucleotide-binding oligomerization domain-like receptor (NOD)2, tumor necrosis factor receptor (TNFR), and interleukin (IL)-1R. In addition, NF-κB activates NLRP3 gene transcription. The second step involves various concomitant molecular mechanisms. Extracellular ATP induces P2×7-dependent pore formation on the cell membrane, which allows K+ efflux depletion and opening a pannexin-1 channel, through which PAMPs and DAMPs enter in the cell, activating NLRP3. Endocitosis of dissimilar agonists, including crystalized cholesterol and uric acid, results in lysosomal disruption, which also leads NLRP3 activation. Additionally, reactive oxygen species (ROS) leads to thioredoxin dissociation, which binds to the NLRP3 inflammasome to trigger its activation. The NLRP3 inflammasome is composed of an inflammasome sensor NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC) and the precursor pro-caspase1: when activated, NLRP3 components cause the activation of caspase-1, which leads to the maturation and secretion of proinflammatory cytokines including IL-1β and IL-18.

Figure 2

Gut–liver axis during cholangiopathies. In normal conditions, primary bile acids (P-BA) reach the small intestine where they directly influence the microbiota composition, mainly by blocking bacterial overgrowth. BA are actively reabsorbed in the terminal ileum via the apical sodium-dependent bile acid transporter (ASBT) and activate farnesoid X receptor (FXR), which, in turn, causes Fgf-19 secretion and direct effects on mucosal defense. In the colon, bacterial metabolization produces a wide variety of secondary bile acids (S-BA), which also enter the portal circulation. Cholangiopathies, which alter the normal bile flow or composition, may interfere with all these processes, ultimately causing dysbiosis and an increased or qualitatively altered PAMPs delivery to the liver via the portal circulation.