Nucleotide signalling during inflammation

Extracellular ATP released from cells during inflammatory responses predominantly functions as a signalling molecule through the activation of purinergic P2 receptors and contributes to both beneficial and detrimental inflammatory responses; this review examines P2 receptor signalling via ATP and its effect on the outcome of inflammatory and infectious diseases. Two sides to purinergic signalling The role of purinergic signalling events in the context of inflammatory diseases is ambivalent: purinergic P2 receptors, activated by ATP and some other nucleotides, are critical in mounting an appropriate inflammatory response against invading pathogens or tumours, yet P2X/P2Ysignalling can cause the initiation and perpetuation of chronic inflammation in conditions such as asthma, chronic lung diseases, or inflammatory bowel disease. This Review focuses on the health aspects of the complex biology of ATP receptor signalling. The authors conclude that pharmacological amplification of extracellular ATP signalling holds promise as a treatment for cancer and infectious disease and that strategies that block P2 receptor signalling, promote extracellular conversion of ATP to adenosine and activate adenosine receptors could be effective in treating acute or chronic inflammatory diseases. Inflammatory conditions are associated with the extracellular release of nucleotides, particularly ATP. In the extracellular compartment, ATP predominantly functions as a signalling molecule through the activation of purinergic P2 receptors. Metabotropic P2Y receptors are G-protein-coupled, whereas ionotropic P2X receptors are ATP-gated ion channels. Here we discuss how signalling events through P2 receptors alter the outcomes of inflammatory or infectious diseases. Recent studies implicate a role for P2X/P2Y signalling in mounting appropriate inflammatory responses critical for host defence against invading pathogens or tumours. Conversely, P2X/P2Y signalling can promote chronic inflammation during ischaemia and reperfusion injury, inflammatory bowel disease or acute and chronic diseases of the lungs. Although nucleotide signalling has been used clinically in patients before, research indicates an expanding field of opportunities for specifically targeting individual P2 receptors for the treatment of inflammatory or infectious diseases.