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A long-shared evolutionary history is congruent with the multiple roles played by purinergic signaling in viral infection, replication and host responses that can assist or hinder viral functions. An overview of the involvement of purinergic signaling among a range of viruses is compared and contrasted with what is currently understood for SARS-CoV-2. In particular, we focus on the inflammatory and antiviral responses of infected cells mediated by purinergic receptor activation. Although there is considerable variation in a patient's response to SARS-CoV-2 infection, a principle immediate concern in Coronavirus disease (COVID-19) is the possibility of an aberrant inflammatory activation causing diffuse lung oedema and respiratory failure. We discuss the most promising potential interventions modulating purinergic signaling that may attenuate the more serious repercussions of SARS-CoV-2 infection and aspects of their implementation. [ABSTRACT FROM AUTHOR]

Eosinophils are major effector cells against parasites, fungi, bacteria, and viruses. However, these cells also take part in local and systemic inflammation, which are central to eczema, atopy, rhinitis, asthma, and autoimmune diseases. A role for eosinophils has been also shown in vascular thrombotic disorders and in cancer. Many, if not all, above-mentioned conditions involve the release of intracellular nucleotides (ATP, ADP, UTP, etc.) and nucleosides (adenosine) in the extracellular environment. Simultaneously, eosinophils further release ATP, which in autocrine and paracrine manners, stimulates P2 receptors. Purinergic signaling in eosinophils mediates a variety of responses including CD11b induction, ROI production, release of granule contents and enzymes, as well as cytokines. Exposure to extracellular ATP also modulates the expression of endothelial adhesion molecules, thereby favoring eosinophil extravasation and accumulation. In addition, eosinophils express the immunosuppressive adenosine P1 receptors, which regulate degranulation and migration. However, pro-inflammatory responses induced by extracellular ATP predominate. Due to their important role in innate immunity and tissue damage, pharmacological targeting of nucleotide- and nucleoside-mediated signaling in eosinophils could represent a novel approach to alleviate eosinophilic acute and chronic inflammatory diseases. These innovative approaches might also have salutary effects, particularly in host defense against parasites and in cancer. [ABSTRACT FROM AUTHOR]

Viral diseases represent a major global problem in human health, with high morbidity and mortality. Despite recent progress in antiviral treatments, several viral diseases are still not controlled and millions suffer from them every year. It has recently emerged that purinergic signaling participates in viral infection and replication. Furthermore, stimulation of purinergic receptors in infected cells also induces inflammatory and antiviral responses, thus contributing to the host antiviral defense. Here we review the multiple roles played by the purinergic signaling network in cell–virus interactions that can lead either to viral maintenance in the cells or, by contrast, to stronger antiviral responses, and discuss potential future applications of purinergic signaling modulation for the treatment of viral diseases. Highlights Viral infection induces the release of intracellular nucleotides (ATP, UTP) into the extracellular fluid. Autocrine activation of purinergic receptors expressed by host cells promotes viral entry and the replication of some viruses. Accordingly, inhibition of purinergic receptors impairs viral infection and the production of viral particles. Pharmacological stimulation of eukaryotic cells with ATP or massive nucleotide release due to extensive cell damage impairs cell–virus interaction and stimulates antiviral responses such as chemotaxis, transcription of antiviral cytokine genes, and the release of inflammatory mediators. Modulation of purinergic receptors expressed by immune cells might reduce the inflammatory responses and exacerbation of disease symptoms occurring as a consequence of the viral infection, such as in the case of asthma, cardiac inflammation, and neurological impairment, thus ameliorating the patient's condition. Targeting of purinergic signaling may represent a new possibility to control viral infections and the pathological consequences of viral diseases. [ABSTRACT FROM AUTHOR]

Nucleotides and nucleosides have emerged as important modulators of tumor biology. Recently acquired evidence shows that, when these molecules are released by cancer cells or surrounding tissues, they act as potent prometastatic factors, favoring tumor cell migration and tissue colonization. Therefore, nucleotides and nucleosides should be considered as a new class of prometastatic factors. In this review, we focus on the prometastatic roles of nucleotides and discuss future applications of purinergic signaling modulation in view of antimetastatic therapies. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) are small non-coding RNA molecules capable of silencing mRNA targets. miRNA dysregulation has been linked to cancer development, cardiovascular and neurological diseases, lipid metabolism, and impaired immunity. Therefore, miRNAs are gaining interest as putative novel disease biomarkers and therapeutic targets. Recent studies have shown that purinergic surface receptors activated by extracellular nucleotides (ATP, ADP, UTP, UDP), and by nucleosides such as adenosine (ADO), are subject to miRNA regulation. This opens a new and previously unrecognized opportunity to modulate the purinergic network with the aim of avoiding abnormal activation of specific receptor subtypes. miRNA technology will hopefully contribute strategies to prevent purinergic-mediated tissue damage in conditions of neurodegeneration, atherosclerosis, transplantation, and even neoplasia. [ABSTRACT FROM AUTHOR]

Migration and positioning of immune cells is fundamental for their differentiation and recruitment at sites of infection. Besides the fundamental role played by chemokines and their receptors, recent studies demonstrate that a complex network of purinergic signaling events plays a key role in these trafficking events. This process includes the release of nucleotides (such as ATP and ADP) and subsequent autocrine and paracrine signaling events through nucleotide receptors. At the same time, surface-expressed ectoapyrases and nucleotidases convert extracellular nucleotides to adenosine, and adenosine signaling events play additional functional roles in leucocyte trafficking. In this review we revisit classical paradigms of inflammatory cell trafficking in the context of recent studies implicating purinergic signaling events in this process. [ABSTRACT FROM AUTHOR]

Cell surface expression of specific receptors and ecto-nucleotidases makes extracellular nucleotides such as ATP, ADP, UTP, and adenosine suitable as signaling molecules for physiological and pathological events, including tissue stress and damage. Recent data have revealed the participation of purinergic signaling in atherosclerosis, depicting a scenario in which, in addition to some exceptions reflecting dual effects of individual receptor subtypes, adenosine and most P1 receptors, as well as ecto-nucleotidases, show a protective, anti-atherosclerotic function. By contrast, P2 receptors promote atherosclerosis. In consideration of these findings, modulation of purinergic signaling would represent an innovative and valuable tool to counteract atherosclerosis. We summarize recent developments on the participation of the purinergic network in atheroma formation and evolution. [ABSTRACT FROM AUTHOR]

Extracellular ATP, released upon microbial infection, cell damage, or inflammation, acts as an alert signal toward immune cells by activating P2 receptors. The nucleotide causes microvesicle (MV) shedding from immune and nonimmune cells. Here, we show that IL-18 associates with MVs shed by human ex vivo macrophages upon P2X receptor stimulation. MV shedding was potently induced by ATP and by the P2X7 agonist 3′-benzoylbenzoyl adenosine 5′-triphosphate, while it was greatly reduced by P2X irreversible inhibitor-oxidized ATP and by the specific P2X7 inhibitors KN-62, A-740003, and A-438079. Peculiarly, the P2X7 subtype was highly present in the MVs, while on the contrary the P2X3 and P2X4 subtypes were almost absent. The Ca2+ ionophore A23187 mimicked the effect of 3′-benzoylbenzoyl adenosine 5′-triphosphate suggesting that an intracellular Ca2+ increase was sufficient to evoke MV shedding. Caspase inhibitors Ac-YVAD-CMK or Z-YVAD-CMK did not block the cleavage of MV-associated pro-IL-18. Pro-IL-18 formation in macrophages did not require pretreatment of cells with LPS, as the procytokine was already present in unprimed macrophages and did not decrease by incubating cells with the LPS-binding antibiotic polymyxin B nor with the TLR-4 intracellular inhibitor CLI-095. These data reveal a nucleotide-based mechanism responsible for the shedding of MV to which IL-18 is associated. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic inflammatory disease of the skin associated with systemic and joint manifestations and accompanied by comorbidities, such as metabolic syndrome and increased risk of cardiovascular disease. Psoriasis has a strong genetic basis, but exacerbation requires additional signals that are still largely unknown. The clinical manifestations involve the interplay between dendritic and T cells in the dermis to generate a self-sustaining inflammatory loop around the TNFα/IL-23/IL-17 axis that forms the psoriatic plaque. In addition, in recent years, a critical role of keratinocytes in establishing the interplay that leads to psoriatic plaques' formation has re-emerged. In this review, we analyze the most recent evidence of the role of keratinocytes and danger associates molecular patterns, such as extracellular ATP in the generation of psoriatic skin lesions. Particular attention will be given to purinergic signaling in inflammasome activation and in the initiation of psoriasis. In this phase, keratinocytes' inflammasome may trigger early inflammatory pathways involving IL-1β production, to elicit the subsequent cascade of events that leads to dendritic and T cell activation. Since psoriasis is likely triggered by skin-damaging events and trauma, we can envisage that intracellular ATP, released by damaged cells, may play a role in triggering the inflammatory response underlying the pathogenesis of the disease by activating the inflammasome. Therefore, purinergic signaling in the skin could represent a new and early step of psoriasis; thus, opening the possibility to target single molecular actors of the purinome to develop new psoriasis treatments. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a widespread neurodegenerative pathology responsible for about 70% of all cases of dementia. Adenosine is an endogenous nucleoside that affects neurodegeneration by activating four membrane G protein-coupled receptor subtypes, namely P1 receptors. One of them, the A2A subtype, is particularly expressed in the brain at the striatal and hippocampal levels and appears as the most promising target to counteract neurological damage and adenosine-dependent neuroinflammation. Extracellular nucleotides (ATP, ADP, UTP, UDP, etc.) are also released from the cell or are synthesized extracellularly. They activate P2X and P2Y membrane receptors, eliciting a variety of physiological but also pathological responses. Among the latter, the chronic inflammation underlying AD is mainly caused by the P2X7 receptor subtype. In this review we offer an overview of the scientific evidence linking P1 and P2 mediated purinergic signaling to AD development. We will also discuss potential strategies to exploit this knowledge for drug development. [ABSTRACT FROM AUTHOR]