The P2X7 Receptor in Inflammatory Diseases: Angel or Demon?

Luiz E B Savio,Robson Coutinho-Silva,Cleide Gonçalves Da Silva,Paola De Andrade Mello

doi:10.3389/fphar.2018.00052

Abstract

Under physiological conditions, adenosine triphosphate (ATP) is present at low levels in the extracellular milieu, being massively released by stressed or dying cells. Once outside the cells, ATP and related nucleotides/nucleoside generated by ectonucleotidases mediate a high evolutionary conserved signaling system: the purinergic signaling, which is involved in a variety of pathological conditions, including inflammatory diseases. Extracellular ATP has been considered an endogenous adjuvant that can initiate inflammation by acting as a danger signal through the activation of purinergic type 2 receptors—P2 receptors (P2Y G-protein coupled receptors and P2X ligand-gated ion channels). Among the P2 receptors, the P2X7 receptor is the most extensively studied from an immunological perspective, being involved in both innate and adaptive immune responses. P2X7 receptor activation induces large-scale ATP release via its intrinsic ability to form a membrane pore or in association with pannexin hemichannels, boosting purinergic signaling. ATP acting via P2X7 receptor is the second signal to the inflammasome activation, inducing both maturation and release of pro-inflammatory cytokines, such as IL-1β and IL-18, and the production of reactive nitrogen and oxygen species. Furthermore, the P2X7 receptor is involved in caspases activation, as well as in apoptosis induction. During adaptive immune response, P2X7 receptor modulates the balance between the generation of T helper type 17 (Th17) and T regulatory (Treg) lymphocytes. Therefore, this receptor is involved in several inflammatory pathological conditions. In infectious diseases and cancer, P2X7 receptor can have different and contrasting effects, being an angel or a demon depending on its level of activation, cell studied, type of pathogen, and severity of infection. In neuroinflammatory and neurodegenerative diseases, P2X7 upregulation and function appears to contribute to disease progression. In this review, we deeply discuss P2X7 receptor dual function and its pharmacological modulation in the context of different pathologies, and we also highlight the P2X7 receptor as a potential target to treat inflammatory related diseases.

Highlights

Adenosine triphosphate (ATP) has long been known as the intracellular energy currency molecule of the cell
In a mouse model where subcutaneous L. amazonensis infection is induced by subcutaneous injection of the parasite in the footpad, genetic deletion of P2X7 receptor resulted in increased cell infiltration, higher IFN-γ levels, and low concentrations of IL-17 and TGF-β in the footpad, suggesting an excessive pro-inflammatory response
ATP-P2X7 receptor signaling boosts the immune system in the context of pathogen infections, activates microbicidal mechanisms, and induces the production of inflammatory mediators in phagocytic cells, as well as modulates adaptive immune responses

Summary

Introduction

Adenosine triphosphate (ATP) has long been known as the intracellular energy currency molecule of the cell. The role of P2X7 receptor in activation of microbicidal mechanisms and production of inflammatory mediators in phagocytic cells, as well as modulation of adaptive immune responses to bacterial infection, have been extensively studied (Coutinho-Silva and Ojcius, 2012; Morandini et al, 2014b; Di Virgilio et al, 2017). ATP, acting through P2X7 receptor, decreases bacterial load in macrophages and epithelial cells infected with different Chlamydia species and strains (Coutinho-Silva et al, 2001b, 2003b; Darville et al, 2007) by overriding Chlamydiae’s evasion mechanisms.

Results

Conclusion