P2X receptors and lipids interact to modulate inflammation

P2X receptors are purinergic receptors activated in the presence of extracellular ATP. These receptors are involved in the pathogenesis of various diseases, including inflammatory diseases, and are also associated with pain. These ionotropic receptors are activated when ATP is released during the inflammatory process. This can occur because, during the inflammatory process, phospholipase A₂ is activated, releasing arachidonic acid, which is converted by COX-1 and COX-2 into prostaglandins or thromboxanes. In this context, prostaglandins sensitize cells, leading them to release ATP, which binds to P2X receptors, thereby activating their ion channels. These channels can act in various ways: P2X₄ is involved in neuropathic pain, whereas P2X₇ receptors can activate the NLRP3 inflammasome, which, in turn, induces IL-1β release and activates the COX pathway, generating an inflammatory cycle. In addition to prostaglandins, other bioactive lipids are also associated with increased expression of P2X receptors, such as leukotrienes and thromboxanes, which can increase Ca²⁺ influx, facilitating the release of extracellular ATP. Bioactive lipids, such as resolvins, lipoxins, maresins, and protectins, which have anti-inflammatory effects and promote homeostasis, can attenuate inflammation. They act indirectly on P2X receptors by controlling the inflammatory process, thereby decreasing ATP release and lowering P2X receptor expression. There are also lipids that structurally assist in P2X receptor activity, such as cholesterol and ceramides. Ceramides also play a role in the cell signaling process, inducing apoptosis. This review clarifies mechanisms of interaction between purinergic receptors P2X family and bioactive lipids, therefore modulating the inflammatory response.