Purinergic regulation of the immune system

Key Points ATP, ADP and other nucleotides can be released by stressed or apoptotic cells into the extracellular environment. They function as autocrine and paracrine signalling molecules by activating cell-surface purinergic receptors. Activation of purinergic signalling pathways can have both pro- and anti-inflammatory effects. During the acute stages of tissue injury, purinergic signalling can promote the recruitment and activation of leukocytes to the damaged site. At later times, purinergic signalling dampens inflammation and promotes wound healing. Drugs that target purinergic receptors are being developed as potential therapeutics to treat patients with inflammatory disorders, autoimmune diseases or cancer. This Review focuses on how purinergic signalling pathways regulate both innate and adaptive immune responses. The authors discuss the potential of targeting purinergic signalling pathways for the treatment of ischaemia, organ transplantation, autoimmunity and cancer. Cellular stress or apoptosis triggers the release of ATP, ADP and other nucleotides into the extracellular space. Extracellular nucleotides function as autocrine and paracrine signalling molecules by activating cell-surface P2 purinergic receptors that elicit pro-inflammatory immune responses. Over time, extracellular nucleotides are metabolized to adenosine, leading to reduced P2 signalling and increased signalling through anti-inflammatory adenosine (P1 purinergic) receptors. Here, we review how local purinergic signalling changes over time during tissue responses to injury or disease, and we discuss the potential of targeting purinergic signalling pathways for the immunotherapeutic treatment of ischaemia, organ transplantation, autoimmunity or cancer.