Purinergic signaling in hepatic disease

Abstract

Extracellular purines (ATP and adenosine) are ubiquitous intercellular messengers. During tissular damage, they function as damage-associated molecular patterns (DAMPs). In this context, purines announce tissue alterations to initiate a reparative response that involve the formation of the inflammasome complex and the recruitment of specialized cells of the immune system. The present review focuses on the role of the purinergic system in liver damage, mainly during the onset and development of fibrosis. After hepatocellular injury, extracellular ATP promotes a signaling cascade that ameliorates tissue alterations to restore the hepatic function. However, if cellular damage becomes chronic, ATP orchestrates an aberrant reparative process that results in severe liver diseases such as fibrosis and cirrhosis. ATP and adenosine, their receptors, and extracellular ectonucleotidases are mediators of unique processes that will be reviewed in detail.

The P2X7 Receptor and NLRP3 Axis in Non-Alcoholic Fatty Liver Disease: A Brief Review

“…In agreement with this observation, in vitro studies have shown that IL-1β treatment induced lipid accumulation in hepatocytes and the activation of fibrogenesis in hepatic stellate cells [28,37]. In the liver, hepatocytes, stellate, and Kupffer cells all express the NLRP3 inflammasome being activated after liver injury to determine the maturation and release of IL-1β, IL-18, and the following cascade of other inflammatory cytokines, favoring liver inflammation and fibrosis [38].…”

“…The discovery of the NLRP3 inflammasome, together with the role of ATP and P2X7 receptors in the processing and release of mature IL-1β, has provided the connection between extracellular ATP, P2X7 receptor, NLRP3 inflammasome, and IL-1β release and the activation and amplification of the inflammatory process. To this regard NLRP3 activation has been described as a "two-step" process: the first is via an NFkB activator as well as LPS, while the second step is mainly via the so-called DAMPs, distinct molecules released by damaged cells acting as alert signals to trigger the innate immune response [38]. As detailed above, among the different DAMPs extracellular ATP (via the activation of the P2X7 receptor on target cells) is one of the most studied, although other activators have been reported, such as reactive oxygen species (ROS), crystals, or large particles [27,34].…”

“…To this regard, within the liver, many different cell types express NLRP3 inflammasome, from hepatocytes to Kupffer and stellate cells and endothelial cells [27,28], further confirming the reported observations. In particular, stellate cells represent the mesenchymal liver cells located in the Disse space, playing a primary role in the fibrogenetic process within the liver, promoting the excessive accumulation of extracellular matrix and type I collagen leading to liver fibrosis [38,54]. To this regard, it has been previously shown that P2X7R is involved in ATP activation of stellate cells via activation of NLRP3 inflammasome [55] and might also mediate the activation of stellate cells by leptin in non-alcoholic steatohepatitis [56].…”

“…Thus the targeting of this purinergic pathway might be a promising therapeutical strategy to extinguish the inflammatory process activated after liver injury. Since the blockade of the P2X7 receptor in experimental animals (via P2X7 receptor gene deletion or using pharmacological agents) results in reduced fat accumulation in the liver, reduced NLRP3 activation and IL-1β production and release, reduced inflammation, reduced liver steatosis evolution to NASH, and reduced liver fibrosis, it is possible to hypothesize that the P2X7 receptor/NLRP3 axis might be an effective therapeutical target to tackle liver steatosis and the fibrotic evolution of NASH [38]. A number of different pharmacological molecules and biological agents have been developed to block the P2X7 receptor/NLRP3 axis [57][58][59] and are actively utilized in experimental studies in many different diseases in humans, from rheumatoid arthritis to chronic obstructive pulmonary disease and Crohn's disease (see [12] and the references therein).…”

Therapeutic Nanobodies Targeting Cell Plasma Membrane Transport Proteins: A High-Risk/High-Gain Endeavor

“…Drugs that selectively target P2X4 channels equally offer therapeutic potential [ 105 , 106 ]. P2X4 channels mainly mediate the trafficking of calcium ions in response to ATP and are involved in different pathologies [ 105 , 107 , 108 , 109 ]. Given the lack of specific and potent P2X4-antagonists, studies have focused on the generation of nanobodies directed towards P2X4 [ 84 ].…”