A rationale for targeting the P2X7 receptor in Coronavirus disease 19

Abstract

Severe pneumonia which shares several of the features of acute respiratory distress syndrome (ARDS) is the main cause of morbidity and mortality in Coronavirus disease 19 (Covid-19) for which there is no effective treatment, so far. ARDS is caused and sustained by an uncontrolled inflammatory activation characterized by a massive release of cytokines (cytokine storm), diffuse lung oedema, inflammatory cell infiltration, and disseminated coagulation. Macrophage and T lymphocyte dysfunction plays a central role in this syndrome. In several experimental in vitro and in vivo models, many of these pathophysiological changes are triggered by stimulation of the P2X7 receptor. We hypothesize that this receptor might be an ideal candidate to target in Covid-19-associated severe pneumonia. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID-19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc.

FIGURE 1

Central role of the P2X7 receptor (P2X7R) in Sars‐Cov‐2‐dependent lung inflammation. Sars‐Cov‐2 infects lung mononuclear phagocytes, apart from the epithelial cells, triggering massive ATP release which feeds back on the P2X7 receptors expressed on macrophages and antigen‐presenting cells (APCs). Activation of P2X7 receptors down‐modulates MHC‐I expression and at the same time promotes IL‐6 release, NLRP3‐mediated IL‐1β and IL‐18 release, VEGF secretion, and thus lung oedema. Release of several other cytokines and chemokines is also promoted by P2X7 receptor activation. Stimulation of P2X7 receptors on APC‐stimulated T lymphocytes (cytotoxic T lymphocytes; CTLs) causes exhaustion and T cell polarization. The combined effect of all these processes promotes the pathophysiological changes typical of ARDS