NLR family pyrin domain containing 3 (NLRP3) inflammasome and P2X purinoceptor 7 (P2X7) receptor (NLRP3/P2X7)

The NLR family pyrin domain containing 3 (NLRP3) inflammasome and the P2X purinoceptor 7 (P2X7) receptor constitute a major signaling axis in the innate immune system. The P2X7 receptor is a trimeric, ligand-gated ion channel that is activated by high concentrations of extracellular adenosine triphosphate (ATP), which serves as a damage-associated molecular pattern (DAMP) [1, 6]. Activation of P2X7 leads to a rapid efflux of potassium ions (K+), which is recognized as a critical second signal for the assembly of the NLRP3 inflammasome complex [2, 3]. This complex, consisting of the NLRP3 sensor, the ASC adaptor protein, and pro-caspase-1, facilitates the maturation and secretion of the potent pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) [3, 5]. Chronic or excessive activation of this axis is linked to various inflammatory, metabolic, and neurodegenerative diseases, including rheumatoid arthritis, gout, type 2 diabetes, and Alzheimer's disease [4, 5]. Therapeutic strategies involve small-molecule inhibitors that either block the P2X7 receptor to prevent the activation signal or directly inhibit the NLRP3 protein to halt inflammasome assembly [2, 5].

Other names

P2X7-NLRP3 signaling axisP2RX7-NLRP3 pathwayPurinergic P2X7 receptor-NLRP3 inflammasome complexATP-P2X7-NLRP3 axis

The P2X7 receptor acts as a gatekeeper for NLRP3 inflammasome activation; extracellular ATP binds to P2X7, causing potassium (K+) efflux, which is a prerequisite for NLRP3 assembly. Drugs targeting this axis either antagonize the P2X7 receptor to block the initial trigger or directly inhibit the NLRP3 protein to prevent the formation of the inflammasome complex and the subsequent release of pro-inflammatory cytokines IL-1β and IL-18 [2, 3, 5].