The role of the purinergic P2X7 receptor in inflammation

Abstract

The inflammatory process, orchestrated against a variety of injurious stimuli, is composed of three inter-related phases; initiation, propagation and resolution. Understanding the interplay between these three phases and harnessing the beneficial properties of inflammation whilst preventing its damaging effects, will undoubtedly lead to the advent of much needed therapies, particularly in chronic disease states. The P2X7 receptor (P2X7R) is increasingly recognised as an important cell surface regulator of several key inflammatory molecules including IL-1beta, IL-18, TNF-alpha and IL-6. Moreover, as P2X7R-dependent cytokine production is driven by activating the inflammasome, antagonists of this receptor are likely to have therapeutic potential as novel anti-inflammatory therapies. The function of the P2X7R in inflammation, immunity and its potential role in disease will be reviewed and discussed.

Figure 1

Summary of the production of active IL-1β. This process can be divided into 3 stages. Stage 1: LPS stimulates monocytes/macrophages (M∅) to produce pro-ICE and pro-IL-1β. Stage 2: ATP stimulates the P2X₇R expressed on M∅ to cause a fall in intracellular K⁺ concentration ([K⁺]_i) which in turn converts pro-ICE to ICE. Stage 3: LPS-primed M∅ following ATP stimulation results in activated ICE which converts inactive pro-IL-β to active IL-1β. It should be noted that this process is intracellular and the figure is for illustrative purposes only (see text for references).

Figure 2

Possible outcomes of an inflammatory response. Tissue damage (inflammation initiation) can lead to cell death by apoptosis or necrosis. The balance between these two types of cell death can determine the outcome of the inflammatory response e.g. propagation (leading to chronic inflammation) or resolution. Resolution is more common when cell death is predominantly apoptotic, however, the phagocytosis of apoptotic or necrotic cells is also an important determinant of the outcome of inflammation. As can be seen, the P2X₇R may be critical to determining the outcome of an inflammatory response.

Figure 3

Diagrammatic representation of the interplay between inflammatory mediators and cells. Tissue damage or inflammatory stimuli results in ATP release which activates the P2X₇R causing eosinophils to release IL-8 which amplifies the initial inflammatory response.