Imapct of P2X4 and P2X7 Purinergic Receptors in Liver Repair – PuReLiRe

The biological processes of tissue repair are widely spread among living organisms, allowing them to restore their integrity after partial loss of cells or organs. A finely tuned interplay between fundamental processes of regeneration, inflammation and fibrogenesis underlies the final outcome of tissue repair after acute and, even more, chronic injury. In the liver context, even though regeneration capacity is huge, tissue repair during chronic injury (viral, toxic, autoimmune…) can lead to hepatic fibrosis, a wound healing response highlighting an unfavorable balance between regeneration and scaring. Liver fibrosis ultimately leads to increased morbidity and mortality with the progressive appearance of cirrhosis and its related risk of cancer. An important, although largely unexplored feature is that after injury and during liver repair process, liver functions have to be maintained to fulfill the peripheral demand. This is particularly critical for bile secretion, which has to be finely tuned in order to preserve liver parenchyma from bile-induced injury. However, mechanisms allowing the liver to maintain biliary homeostasis during repair after injury are not completely understood. The only definitive treatment at an advanced stage of hepatic fibrosis (cirrhosis) is liver transplant, although the deficit/shortage in organ grafts put forward the need for novel therapies to stimulate regeneration and prevent and/or reverse fibrosis. Besides cytokines and growth factors, extracellular nucleotides (ATP and its degradation products) as purinergic receptors ligands, constitute an unrecognized, although powerful, signaling network during liver regeneration and repair. Virtually all cell types in multicellular organisms, under diverse physical or chemical stimuli, can release ATP in the extracellular medium, which can bind to membrane purinergic receptors (“P2” receptors) to elicit a wide array of biological responses. All types of liver cells (hepatocytes, endothelial cells, Kupffer cells, stellate cells, cholangiocytes) express purinergic receptors including ionotropic P2X and metabotropic P2Y subtypes. Therefore, extracellular ATP that is released in a paracrine manner in its microenvironment can target any hepatic cell. Our previous studies allowed us i) to highlight (with other groups) that all types of liver cells express purinergic receptors, in particular P2X4 and P2X7 that are strongly expressed by hepatocytes and Kupffer cells, ii) to demonstrate that partial hepatectomy stimulates an immediate and massive liver ATP release in rats and humans; iii) that ATP release participates to the regenerative response. Given that cell death and suffering leads to a release of ATP in extracellular medium, any hepatic cell during liver injury can be targeted by extracellular ATP in a paracrine manner, with potential consequences on processes of inflammation, regeneration, biliary homeostasis and ultimately fibrosis development.
We obtained preliminary data indicating that purinergic signaling, through P2X4 and P2X7 receptors, have determining impact on the final outcome (fibrosis) of biliary type liver injury in mice. Also based on our preliminary data, mechanisms through which P2X4 and P2X7 act in this experimental setting may include regulation of liver regeneration, inflammation and biliary homeostasis. Our general objective is to determine the impact of purinergic signaling in the pathophysiology of liver repair through P2X4 and P2X7 receptors, in experimental mouse models and in human patients. Our proposal will focus on: 1. Contribution of P2X4 and P2X7 in liver inflammatory processes during liver repair. 2. Regulatory role of P2X4 and P2X7 in maintaining biliary homeostasis. Based on collaborative studies from the two partners of the present proposal, new therapeutic options may be drawn to modulate cell regeneration, inflammatory processes and/or biliary homeostasis in liver pathophysiology.