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.

Keywords: Ectonucleotidases; Fibrosis; Inflammation; Liver; Purinergic receptors.

Fig. 1

Pro-inflammatory responses mediated by purinergic signaling associated with hepatocellular damage. Upon hepatocellular injury or stress (a), damaged hepatocytes release DAMPs, particularly ATP, into the extracellular space (b). This nucleotide exerts its actions by interacting with specific P2X (mainly P2X7 and P2X4 in the liver) and P2Y membrane receptors (mainly P2Y2 in the liver). The autocrine/paracrine purinergic actions promote the production and release of pro-inflammatory molecules by the own hepatocyte or by other liver cell types (c), such as hepatic stellate cells (HSCs) and Kupffer cells, to induce their activated phenotype (d, e). Then, additional ATP and other pro-inflammatory signals released from activated HSCs and Kupffer cells act as chemoattractants for immune cells such as neutrophils and macrophages (f). At the same time, ATP is irreversibly turned into adenosine (ADO), which also contributes to the cellular events leading to liver fibrosis by acting through P1 receptors (g). Together, these signals support the wound-healing response that, after some time, promotes hepatocellular plastic adaptations, tissular remodeling, and chronic inflammation (h), culminating in a fibrotic state. In the picture, red arrows indicate released compounds to the extracellular space acting in autocrine or paracrine fashion, whereas blue arrows indicate phenotypic changes of the participating cells