Interestingly as observed with Treg cells adenosine can regu

Interestingly, as observed with Treg cells, adenosine can regulate the function of Breg cells, a subset of immunosuppressive cells that support immunological tolerance [115]. In particular, Bregs were able to regulate both their own function and T cell activity via an adenosine signaling originating from the enzymatic degradation of ATP, released in the extracellular space from activated immune cells [116]. Indeed, it has been observed that Breg cells are endowed with CD39, CD73, CD25 but not CD26, thus allowing, in the presence of extracellular ATP, the production of adenosine by Bregs to a much larger extent than Tregs [116]. The biologic significance of this ability of Pyronaridine Tetraphosphate to produce adenosine can be appreciated in the context of their interactions with T cells [116]. Under resting condition, Breg cells promoted responses of activated T cells. On the other hand, once activated, Breg cells increase their ability to produce adenosine, becoming strongly suppressive toward T cells [116]. Of note, the ability of Breg cells to counteract T-cell functions depends on the state of their activation and to the microenvironmental context [116].
Conclusions The research efforts of the last four decades have provided a large body of evidence regarding the involvement of adenosine signaling in shaping immune system activity. These studies paved the way to the introduction of both innovative anti-inflammatory tools, such as A3 receptor agonists and immune enhancing agents, such as immune checkpoint blockers in the oncology field (e.g., A2A receptor antagonists and CD73 blockers), some of which have already entered into the clinical arena with encouraging results either in terms of efficacy and safety. However, there are still significant gaps to fill in our understanding about the complex liaison occurring between the adenosine pathway and the immune system aimed to its optimal therapeutic exploitation.
Introduction Adenosine and ATP, acting extracellularly via purinergic-type receptors (Burnstock, 1972, Burnstock and Verkhratsky, 2009), are known to play important roles in numerous biological processes. Among them, adenosine represents an important autocrine modulator of nicotinic cholinergic synaptic activity (Cunha and Sebastião, 1993, Ribeiro et al., 1996, Todd and Robitaille, 2006). At the skeletal neuromuscular junction (NMJ), the extracellular concentration of adenosine is mainly controlled by ATP, co-released at the nerve terminals with acetylcholine (ACh) and converted into adenosine by ectoenzymes. Adenosine itself is also released into the extracellular compartment from muscle cells (Lynge et al., 2001). At rest, the extracellular concentration of adenosine at the NMJ is estimated to be around 10 nM, whereas during muscle contraction, it increases up to the μM range (Smith, 1991, Cunha and Sebastião, 1993). It is now widely accepted that adenosine modulates the release of ACh through the activation of P1-type receptors (P1Rs), known to be expressed presynaptically on cholinergic nerve terminals (Giniatullin and Sokolova, 1998, De Lorenzo et al., 2004, Baxter et al., 2005, Tomàs et al., 2014, Nascimento et al., 2014). Besides this, the presence of postsynaptic P1Rs, and specifically RA2B and RA3 subtypes, has also been recently reported by immunocytochemistry and Western Blotting analysis at the postsynaptic side of the mouse NMJ (Garcia et al., 2013, Garcia et al., 2014). This finding opens a new scenario, with adenosine as a potential endogenous modulator of cholinergic neurotransmission also acting at the postsynaptic level. This intriguing aspect has yet to be investigated. Adenosine can bind to four P1R subtypes, named A1, A2A, A2B and A3 (Fredholm et al., 2011), all G-protein coupled receptors, with a different affinity for the endogenous ligand. A1 and A2A are known as high-affinity P1Rs (in rodent, A1R: Ki = 73 nM, A2AR: Ki = 150 nM), while the A2B and A3 are low-affinity subtypes (in rodent, A2B R: Ki = 5100 nM, A3R: Ki = 6500 nM, reviewed in Fredholm et al., 2011). It is generally accepted that the activation of A1R and A3R inhibits the activity of adenylyl cyclase, while A2A and A2B subtypes increase the activity of the same enzyme. Moreover, all of them can trigger other unknown and often unpredictable signal pathways (Fredholm et al., 2011).