Pathogens, including viruses, have evolved to use host-encoded proteins to infect, replicate, and persist in the host [1]. Several groups recently identified that the Pannexin-1/ATP/purinergic receptor signaling axis is essential for viral entry, replication and associated inflammation [2, 3, 4, 5∗∗]. Purine nucleosides are essential for cellular metabolism but can also be released into the extracellular space for signaling purposes [6,7]. For the past four to five decades, the role of purinergic signaling has been described in several acute and chronic diseases, as well as injury resolution, but its role in emerging diseases has only recently been explored [8, 9, 10, 11, 12, 13].

Extracellular ATP is a strong inflammatory molecule, often referred to as a “danger signal” even at low concentrations. It can be contrasted to its downstream metabolite, adenosine, which has anti-inflammatory properties [14,15]. Functionally, ATP signaling enhances T cell activation and antigen presentation to initiate an immune response and prevent T cell anergy [16, 17, 18]. In healthy conditions, the response to ATP is highly coordinated and transient because purine nucleotides are rapidly degraded by several ectonucleotidases such as CD39 and ectonucleotidase triphosphate diphosphohydrolase (ENTPD-1), which catalyze ATP/ADP into AMP as well as CD73/ecto-5′-nucleotidase (NT5E) further converts AMP into adenosine to prevent purinergic overactivation of the immune system. Thus, in healthy conditions, the half-life of extracellular ATP is extremely short; it is catabolized within minutes [19, 20, 21]. In subsequent sections, we will discuss the function of ATP and purinergic signaling in healthy and pathological conditions to identify novel treatment strategies.

ATP (100 μM) increases dendritic cell maturation markers such as CD54, CD80, CD83, CD86, HLA-DR, and MHC class II by a P2Y11 and P2X7-dependent mechanism to promote antigen presentation and T cell activation [22]. High ATP (100 μM) given along a TLR2 agonist promotes IL-23 secretion resulting in monocytes and Th17 polarization and further DC differentiation [22]. In addition, ATP and purinergic activation enhance the immune response of B cells, monocyte/macrophages, eosinophils, and dendritic cells (DC) [23]. Also, as recently demonstrated in dendritic cells, ATP is a key regulator of cellular migration [24]. Further, high ATP (100 μM) concentrations compromise proper immune T lymphocyte responses by preventing the migration of T lymphocytes in response to CCL19 in a P2X7-dependent manner [25]. In contrast, high ATP (1–50 nM and high ATP, 250 nM) concentrations stimulate Treg proliferation and chemotaxis mediated by P2Y2 activation; however, low ATP concentrations are ineffective at inducing this response [26]. Thus, the number of Tregs is increased by extracellular ATP both by enhancing proliferation and recruiting Tregs on site, but not by converting non-Tregs into Tregs [26].

Interestingly, the activation of CD4+ T lymphocytes with low extracellular ATP levels (250 nM) resulted in the enhancement of IL-2 secretion and triggered CD49b and CD54 expression, both essential in migration and adhesion to endothelium to transmigrate into different tissues for surveillance and in response to infection [26]. In contrast, high ATP levels on activated CD4+ T lymphocytes decreased CD54, CD49b, and CD25 expression, suggesting lymphocyte activation and migration inhibition, particularly in response to CCL19 [25,26]. This mechanism can prevent surveillance and antigen presentation because lymphocytes need a strong interaction with DCs. But also, the downregulation of CD25 induced by high ATP levels affects IL-2-dependent T cell survival and proliferation [26]. High ATP levels can also directly influence cell viability through the overactivation of P2X4 and P2X7, which have been shown to induce apoptosis [27]. Despite the concentration of ATP indicated within the review and the literature can be considered high. ATP is locally released and its rate of degradation is high keeping the final concentration low.

Under pathological conditions, including infection, a large amount of ATP is released from compromised or dying cells, increasing the homeostatic ATP levels and resulting in the overactivation of purinergic receptors and associated signaling [11,14]. Overactivation of the purinergic system has been demonstrated in several chronic conditions such as gout, allergen-driven lung inflammation, chronic obstructive pulmonary disease (COPD), diabetes, inflammatory bowel disease, asthma, and rheumatoid arthritis, as well as in more severe diseases such as cancer, multiple sclerosis, leukemia, and graft-versus-host disease [28∗, 29, 30∗, 31, 32, 33]. Several groups propose that perturbations in the purinergic system mediate chronic inflammatory disease states [34∗, 35∗∗, 36, 37].

Most studies examining the role of ATP on monocytes/macrophages obtained from tumors or tumor-associated macrophages have an M1 (classically activated macrophages) proinflammatory phenotype with anti-tumor activity [38]. M2 (alternatively activated macrophages) secrete the anti-inflammatory cytokine IL-10, resulting in cancer cell survival, proliferation, plasticity, and invasiveness [39]. The M1 phenotype has been characterized by its low expression of ectonucleotidases and slower ATP hydrolysis rate than the M2 phenotype [40]. In macrophages/microglia, millimolar concentrations of ATP promote the production of IL-1β, IL-6, IL-18, CCL2, and TNF-α by a P2X7-dependent mechanism [41, 42, 43].

Similar to the lymphocyte data, low ATP levels and other nucleotides activate G-protein coupled P2YRs to mediate myeloid cell chemotaxis into damaged tissues [44]. Thus, monocyte/macrophage/microglia are differentiated and activated by ATP.

Overall, ATP has profound activation signatures in immune cells in healthy conditions; however, high ATP compromises immune responses, resulting in disease. Nevertheless, most of these mechanisms are unknown. Our laboratory demonstrated that opening Pannexin-1 channels in response to several pathogens mediates ATP secretion and most of these mechanisms will be dicussed below.