Adenosine and Inflammation: Here, There and Everywhere

Abstract

Adenosine is a ubiquitous endogenous modulator with the main function of maintaining cellular and tissue homeostasis in pathological and stress conditions. It exerts its effect through the interaction with four G protein-coupled receptor (GPCR) subtypes referred as A₁, A_2A, A_2B, and A₃ adenosine receptors (ARs), each of which has a unique pharmacological profile and tissue distribution. Adenosine is a potent modulator of inflammation, and for this reason the adenosinergic system represents an excellent pharmacological target for the myriad of diseases in which inflammation represents a cause, a pathogenetic mechanism, a consequence, a manifestation, or a protective factor. The omnipresence of ARs in every cell of the immune system as well as in almost all cells in the body represents both an opportunity and an obstacle to the clinical use of AR ligands. This review offers an overview of the cardinal role of adenosine in the modulation of inflammation, showing how the stimulation or blocking of its receptors or agents capable of regulating its extracellular concentration can represent promising therapeutic strategies for the treatment of chronic inflammatory pathologies, neurodegenerative diseases, and cancer.

Keywords: adenosine; adenosine receptors; chronic inflammatory diseases; immune system; inflammation.

Figure 1

Adenosine metabolism and transport in the extracellular and intracellular milieu. Abbreviations: ATP: adenosine triphosphate; ADP: adenosine diphosphate; AMP: adenosine monophosphate; ADA: adenosine deaminase; AK: adenosine kinase; ENTs: equilibrative nucleoside transporters; ARs: adenosine receptors.

Figure 2

Schematic representation of main actions mediated by adenosine receptors (ARs) in human immune cells. Abbreviations: TNF-α: tumor necrosis factor α; IL: interleukin; MIP: macrophage inflammatory protein; IFN-γ: interferon γ; TGF-β: tissue growth factor β; VEGF: vascular endothelial growth factor; IDO-1: indoleamine 2:3 dioxygenase; COX-2: cyclooxygenase 2; ROS: reactive oxygen species; NF-κB: nuclear factor κ-light-chain-enhancer of activated B cells; ↑: increase; ↓: decrease.