P2X ion channel receptors and inflammation

Abstract

Neuroinflammation limits tissue damage in response to pathogens or injury and promotes repair. There are two stages of inflammation, initiation and resolution. P2X receptors are gaining attention in relation to immunology and inflammation. The P2X7 receptor in particular appears to be an essential immunomodulatory receptor, although P2X1 and P2X4 receptors also appear to be involved. ATP released from damaged or infected cells causes inflammation by release of inflammatory cytokines via P2X7 receptors and acts as a danger signal by occupying upregulated P2X receptors on immune cells to increase immune responses. The purinergic involvement in inflammation is being explored for the development of novel therapeutic strategies.

Keywords: ATP; Cytokines; Inflammasome; P2X4 receptors; P2X7 receptors.

Fig. 1

Release of extracellular adenosine triphosphate (ATP) and adenosine diphosphate (ADP) and activation of ATP (P2) receptors during inflammation. During inflammatory conditions that occur in vascular thrombosis, hypoxia, ischemia, inflammatory bowel disease, and acute lung injury, multiple cell types release nucleotides, typically in the form of ATP or ADP, from the intracellular compartment into the extracellular space. The release of nucleotides includes release of ATP from necrotic cells, pannexin-hemichannel-dependent release of ATP during apoptosis, and release of ATP through connexin hemichannels from activated inflammatory cells such as polymorphonuclear granulocytes (neutrophils). In addition, release of extracellular ATP has been shown to occur through vesicular exocytosis or connexin hemichannels from endothelial and urothelial cells, osteoblasts, and astrocytes, as well as nerves (not shown). An additional source of extracellular nucleotides in inflammatory conditions is provided by activated platelets, which release ATP and ADP through the release of granules and exocytosis. In the extracellular space, these nucleotides function as signalling molecules that can activate P2Y receptors (G protein-coupled receptors) or P2X receptors (ligand-gated ion channels). Examples of nucleotide-receptor signalling in inflammatory conditions include P2Y6- or P2X7-receptor signalling, which mediates vascular inflammation, and P2Y1-, P2X1-, and P2Y12-receptor signalling, which mediate platelet activation. Activation of P2 receptors of the P2Y2 and P2X7 family that are expressed on dendritic cells is thought to play a role in promoting lung inflammation in chronic lung diseases such as asthma (reproduced from [9], with permission from the Massachusetts Medical Society)