Nucleotide signalling during inflammation

Abstract

Inflammatory conditions are associated with the extracellular release of nucleotides, particularly ATP. In the extracellular compartment, ATP predominantly functions as a signalling molecule through the activation of purinergic P2 receptors. Metabotropic P2Y receptors are G-protein-coupled, whereas ionotropic P2X receptors are ATP-gated ion channels. Here we discuss how signalling events through P2 receptors alter the outcomes of inflammatory or infectious diseases. Recent studies implicate a role for P2X/P2Y signalling in mounting appropriate inflammatory responses critical for host defence against invading pathogens or tumours. Conversely, P2X/P2Y signalling can promote chronic inflammation during ischaemia and reperfusion injury, inflammatory bowel disease or acute and chronic diseases of the lungs. Although nucleotide signalling has been used clinically in patients before, research indicates an expanding field of opportunities for specifically targeting individual P2 receptors for the treatment of inflammatory or infectious diseases.

Conflict of interest statement

The authors declare no competing financial interests. Readers are welcome to comment on the online version of the paper.

Figures

Figure 1. Extracellular nucleotide release and signalling during inflammation

During inflammation, multiple cell types release nucleotides, for example ATP or ADP, from their intracellular compartments into the extracellular space. Nucleotides can be released during mechanical injury, necrosis, apoptosis or inflammatory cell activation. Several molecular pathways have been implicated in this process, such as vesicular ADP release from platelets, pannexin-mediated ATP release during apoptosis, and connexin-or pannexin-mediated ATP release from inflammatory cells, such as neutrophils. Extracellular nucleotides function as signalling molecules through the activation of purinergic P2 receptors. These receptors can be grouped into metabotropic P2Y receptors (P2YRs; GPCRs with seven transmembrane-spanning motifs) or ionotropic P2X receptors (P2XRs), which are nucleotide-gated ion channels. Each P2XR is formed by three subunits (P2XR monomers), each of which consists of two transmembrane regions, TM1 and TM2. Binding of three molecules of ATP to the assembled P2X channel causes opening of a central pore. These conformational changes allow for flux of ions such as sodium (Na+), calcium (Ca2+) and potassium (K+) across the membrane. ATP signalling is terminated by the enzymatic conversion of ATP to adenosine through the ectonucleoside triphosphate diphosphohydrolase CD39 (conversion of ATP/ADP to AMP) and the ecto-5′-nucleotidase CD73 (conversion of AMP to adenosine). Similar to ATP, adenosine (A) functions as an extracellular signalling molecule through the activation of purinergic P1 adenosine receptors.

Figure 2. P2Y2R signalling during injury resolution and chronic inflammation

P2Y2R signalling on phagocytes, such as macrophages, contributes to the clearance of apoptotic cells, which release the P2Y2R agonist ATP as a ‘find-me’ signal. P2Y2R-mediated clearance of apoptotic cells and debris contributes to wound healing. Activation of P2Y2R by UTP or ATP promotes mucociliary clearance in the airways via inhibition of the epithelial sodium channel (ENaC), which is associated with concomitant increases in mucin production, surfactant-secretion and ciliary beating. Neutrophil-dependent ATP release and autocrine activation of P2Y2R contributes to purinergic chemotaxis, thereby enhancing bacterial clearance during pneumonia. On the other hand, P2Y2R-mediated release of IL-8 and neutrophil elastase (NE) from neutrophils contributes to the pathogenesis of chronic obstructive lung disease (COPD). ATP-elicited P2Y2R signalling on alveolar epithelial cells or eosinophils causes production of pro-allergic mediators (for example, IL-33, IL-8, eosinophil cationic protein) during allergic airway disease. Similarly, P2Y2R signalling on dendritic cells has a role during the induction and self-perpetuation of asthma.

Figure 3. P2X7R signalling during infection and inflammation

P2X7R is required for mounting an appropriate inflammatory response to defend against invading pathogens, for example during intracellular killing of Mycobacterium tuberculosis by macrophages. Dying tumour cells release ATP, which activates P2X7R expressed on DCs, which in turn promotes the priming of IFN-γ-producing cytotoxic CD8+ T cells that kill cancer cells. On the other hand, P2X7R signalling on DCs and concomitant T-cell priming contributes to allergic disease states, such as CD8+ T-cell-elicited contact dermatitis. DC-mediated T-cell priming under the control of P2X7R signalling has also been shown to promote TH1 responses that are implicated in graft-versus-host disease, which contributes to the rejection of a transplanted organ. Similarly, P2X7R-mediated T-cell priming towards a TH2 response promotes allergic airway disease during asthma. Priming of TH17 cells is critical during psoriasis and contributes to intestinal inflammation as occurs during IBD. P2X7R signalling on enteric neurons or mast cells has been implicated in promoting intestinal inflammation during IBD.