The role of extracellular ATP and purinergic signaling in inflammation. On insults inducing cell damage and stress, cells can release into the extracellular environment nucleotides, such as ATP. Once released, ATP can take part in all the different steps of inflammatory responses. 1. Initiation: after being secreted into the pericellular environment, ATP can act as a danger signal and alert the immune system, thus helping initiate the inflammatory response. 2. Progression: ATP can bind to P2 receptors exposed on the cell membrane of target cells and induce granulocyte and macrophage chemotactic attraction toward the inflammatory focus, as well as activation of antigen-presenting cells. These responses induce the activation of both the innate and the adaptive branches of the immune system, leading to the amplification of the inflammatory response. 3. Resolution: under physiologic conditions, inflammatory responses need to be restrained from self-amplifying without control. To protect tissues from extended damages, anti-inflammatory responses are activated. With specific regard to purinergic signaling, CD39 and CD73 endonucleosidases concur to down-regulate inflammation by hydrolyzing ATP in adenosine, with a double effect: prevent ATP from further activate P2R signaling and increase adenosine concentration, which activates anti-inflammatory responses by binding to P1 receptors.