A potential therapeutic role for P2X7 receptor (P2X7R) antagonists in the treatment of inflammatory diseases

Abstract

Introduction: The P2X7 receptor (P2X7R) has an important role in inflammation and immunity, but until recently, clinical application has been limited by a lack of specific antagonists. Recent studies using P2X7R knockout mice and specific receptor antagonists have shown that the P2X7R is an important therapeutic target in inflammatory diseases.

Areas covered: We have reviewed the current literature on the role of the P2X7R in inflammatory diseases, focusing on potential therapeutic applications of selective P2X7R antagonists as anti-inflammatory agents. Particular emphasis has been placed on the potential role of P2X7R in common inflammatory diseases. The latest developments in Phase I and II clinical trials of P2X7R antagonists are covered.

Expert opinion: Recent studies using gene knockout mice and selective P2X7R antagonists suggest that P2X7R is a viable therapeutic target for inflammatory diseases. However, efficacious P2X7R antagonists for use in clinical studies are still at an early stage of development. Future challenges include: identifying potential toxicity and side effects of treatment, timing of treatment initiation and its duration in chronic inflammatory conditions, optimum dosage and development of a functional assay for P2X7R that would help to guide treatment.

Figure 1. Mechanism of action of the P2X₇ receptor

LPS engages with the Toll receptor 4 (TLR4). This results in activation of NFκB and nuclear transcription of IL-1β. IL-1β mRNA is subsequently translated into the precursor molecule pro- IL-1β within the cytoplasm [1]. IL-18 is transcribed and translated constitutively [2]. LPS ‘primes’ the P2X₇R. On contact with ATP and/or LL37, the P2X₇R forms a non-selective ion pore [2]. This allows the efflux of K⁺ and the influx of Ca²⁺⁺ [3]. The change in membrane potential and intracellular Ca²⁺ and K⁺ results in the assembly of the inflammasome and drives the conversion of pro- caspase-1 into mature caspase-1. Pro- IL-1β and caspase-1 are incorporated into the lysosome. Pro-Il-1β is converted into mature IL-1β by the action of caspase-1 within the lysosome and is released into the extracellular environment [4]. Caspase-1-dependent processing of pro-IL-1β may occur in the cytosol following activation of P2X7-receptor and may be released via mechanisms independent of the lysosomal pathway (marked with ‘?’) [5,6]. The P2X7 receptor is coupled to a dye uptake pore, pannexin-1, which opens on prolonged stimulation of the P2X₇R [7]. Opening of the pannexin pore allows the passage of hydrophilic solutes into the cell. This is thought to result in cell death [1].

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