The P2X7 receptor/adenosine-generation system: a novel target for the therapy of autoinflammatory diseases

Autoinflammatory diseases are a group of genetic diseases characterized by recurrent fever with inflammation localized to skin, pleura, peritoneum, joints and also eyes, liver, spleen or the nervous system. Sometimes, liver or kidney involvement may lead to death. The most relevant pathogenetic factor in autoinflammatory diseases is the excessive production of inflammatory mediators known as cytokines, notably Interleukin-1beta (IL-1beta). In general, with the exception of a desease known as familial mediterranean fever (FMF), which is relatively common in populations of middle-eastern origin and in Southern Italy, they are rare. These diseases are of increasing interest to physicians and biomedical investigators as there is no available therapy. Our Research Unit has identified in recent years one of the most potent receptors (named P2X7) responsible for IL-1beta maturation and release, and has unveiled the mechanism by which this receptor stimulates the intracellular pathways leading to processing and release of this cytokine. Furthermore, there is increasing awareness that during inflammation the fundamental high-energy intermediate ATP is released into the blood and biological fluids. Extracellular ATP acts as a potent pro-inflammatory mediator, but also as a source for the generation of a potent anti-inflammatory agent named adenosine. There is evidence that a faulty degradation of ATP to adenosine may prevent the activation of a crucial phsyiological anti-inflammatory pathway, thus leading to uncontrolled inflammation. We think that the production of insufficient amounts of adenosine might contribute to the unexplained, repeated, bouts of inflammation typical of autoinflammatory diseases. In this project we will 1) explore the factors that regulate the homeostasis of extracellular ATP in animal models of inflammation; 2) investigate ATP homeostasis and the efficiency of adenosine generation in immune cells from patients affected by autoinflammatory syndromes; 3) test novel anti-inflammatory drugs targeting the P2X7 receptor.