P2 purinergic receptors in systemic lupus erythematosus: from experimental findings to therapeutic perspectives

P2 purinergic receptors are activated by extracellular adenosine triphosphate and other nucleotides released during inflammatory processes, cellular stress responses, and amplification by NETosis, thereby serving as pivotal mediators of both innate and adaptive immunity. In patients with active systemic lupus erythematosus (SLE), emerging evidence highlights the critical roles of distinct P2 receptors: P2RX4 and P2RY11 in initiating the immune response; P2RY2 in orchestrating immune cell recruitment; P2RX7 in promoting pro-inflammatory states coupled with impaired regulatory mechanisms; and P2RY12 as a driver of type I interferon signaling. Therapeutic targeting of these receptors through selective antagonists has demonstrated efficacy in preclinical lupus-prone models to restore regulatory functions (P2RX7), to control inflammation (P2RX7), type I interferon pathway (P2RY12), autoantibody production (P2RX4 and P2RX7), and glomerulonephritis (P2RX4, P2RX7, P2RY2, and P2RY12). In SLE, selective P2 antagonists are under investigation with major challenges regarding cellular specificity, therapeutic efficacy, and side effects.