Open access peer-reviewed chapter
Abstract
In mammalian cells, the purinergic signaling and inflammatory mediators regulate each other. During microbial infection, nucleotides and nucleosides from both dying host cells and pathogens may be recognized by the host receptors. These receptors include purinergic receptors such P2X, P2Y, and A2A, as well Toll-like receptors, and NOD-like receptors. The interaction with most of these receptors activates immune responses, including inflammasome activation, releasing of pro-inflammatory cytokines, reactive nitrogen and oxygen species production, apoptosis induction, and regulation of T cell responses. Conversely, activation of adenosine receptors is associated with anti-inflammatory responses. The magnitude of resultant responses may contribute not only to the host defense but also to the homeostatic clearance of pathogens, or even to the severe progression of infectious diseases. In this chapter, we discuss how the purinergic signaling activation upregulates or downregulates mechanisms in infectious diseases caused by the bacterial, parasite, and viral pathogens, including SARS-CoV-2. As a concluding remark, purinergic signaling can modulate not only infectious diseases but also cancer, metabolic, and cardiovascular diseases, constituting a strategy for the development of treatments.
Keywords
- purinergic receptors
- immune responses
- inflammation
- infectious disease
1. Introduction
The purinergic signaling modulates pathways of both neural and non-neural physiological processes, including immune responses, inflammation, pain, platelet aggregation, endothelium-mediated vasodilation, proliferation, and cell death [1]. Three main components are part of the system. Purinergic: extracellular nucleotides and nucleosides, their receptors, and the ectoenzymes responsible for regulating the levels of these molecules [2]. In addition, nucleotides, nucleosides, and uric acid resulting from the death of infected or injured cells are also recognized by other receptors better known for their role in pathogen recognition as Toll-like receptors (TLRs), and NOD-like receptors (NLRs) [3]. Other immune innate receptors are able to detect nucleic acids (RNA or DNA) from either phagocyted or circulating microbes, including retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), the C-type lectin receptors (CLRs), and cytosolic sensors [4, 5]. All immune cells are able to recognize nucleotides as a danger signal throughout either purinergic or no purinergic receptors. Immediately various immune responses can be activated, such as pro-inflammatory cytokines secretion by macrophages, quimocine production by eosinophils, maturation of dendritic cells (DCs), as well as T and B cells costimulation [6].
Extracellular nucleotides and nucleosides are released, along with many other molecules, from dead cells. Apoptosis and necrosis are the cell death mechanisms that can operate in physiological conditions. Apoptosis is activated by genetically controlled cell signals to modulate cell growth and development, as it is a programmed event. It is an ordered process that does not trigger inflammation. Conversely, necrosis is a not regulated cell death, characterized by the cell content release as a consequence of the effect of diverse environmental factors, leading to higher inflammation around [7]. Furthermore, during infections, some intracellular pathogens require cell lysis, while others have developed mechanisms to prevent cell death during their replication and dissemination outside the infected cell.
ATP is known as a damage signal, released or leaked by injured cells, or a molecular pattern associated with damage [8]. Necrotic cells may use either pannexin channels or connexin hemichannels to release intracellular ATP, and the P2X7R may be involved in this process [6]. Adenosine is a nucleoside that mediates anti-inflammatory and immunosuppressive actions, such as inhibiting the production of pro-inflammatory cytokines and lymphocyte proliferation [9]. In pathological conditions, adenosine plays a protective role acting as an endogenous regulator of innate immunity and in host defense against excessive tissue damage associated with inflammation [10]. The A1 and A2A receptors (A1R and A2AR) are activated by adenosine concentrations in the nanomolar range, while the A2B and A3 receptors (A2BR and A3R) become active only when the extracellular levels of adenosine rise in the micromolar range during periods of inflammation, hypoxia or ischemia [11] (Figure 1). Other nucleosides are recognized by several P2 receptors, which are going to explain later.
Figure 1.
Infected cells release nucleotides and nucleosides. High ATP concentration can induce both dead cell (dashed line, in dendritic cell) and several functions over immune cells as maturation, and quimiotaxis. Low ATP concentration ([ATP]) can induce (arrow) or inhibit (bar-headed line) responses depending on the immune cell. Low adenosine concentration ([ADO]) can induce ROS and NO. High adenosine concentration ([ADO]) inhibit pro-inflammatory cytokine (*Cytokines) expression. Reddish and bluish background means pro-inflammatory and anti-inflammatory context, respectively. Source: The figure 1 design is original and cell vectors were modified from freepik’s:
2. Regulation of extracellular nucleotides and nucleosides
In the context of the immune response, as mentioned, while the extracellular ATP (eATP) exhibits pro-inflammatory and stimulatory effects in the immune system, either appropriate or exacerbated responses [6], adenosine has primarily anti-inflammatory and inhibitory effects [9]. Therefore, the balance between ATP versus adenosine levels is important in modulating cellular immune responses and pathogen survival [12]. The concentrations of extracellular nucleotides and nucleosides are regulated by immune and non-immune cells through the action of enzymes anchored to the cell membrane, with their catalytic site facing the extracellular environment [13]. These enzymes, called ectonucleotidases, hydrolyze extracellular nucleotides into their respective nucleosides to control exacerbated levels of nucleotides and maintain steady-state conditions [12]. Among them, ecto-nucleoside triphosphate diphosphohydrolases (E-NTPDases, CD39, or apyrases), hydrolyzes both ATP and ADP to AMP, in the presence of divalent cations such as calcium and magnesium. Sequentially, the E-5′-nucleotidase (CD73) terminates the ectonucleotidase cascade with the hydrolysis of monophosphate nucleotides, resulting in adenosine. This in turn is hydrolyzed by the enzyme adenosine deaminase (E-ADA), transforming adenosine into inosine, its inactive metabolite [13]. In addition, the ecto-nucleotide pyrophosphatase/phosphodiesterases (E-NPPs) yield free nucleosides. The nitrogenous bases are hydrolyzed from nucleosides by the action of phosphorylases that yield ribose-1-P and free bases. If the nucleosides and/or bases are not re-utilized, the purine bases are further degraded to uric acid [3].
Two important environments for the highly reported purinergic signaling activation are the central nervous system (CNS) and the blood. The principal cell type in the brain involved in ATP degradation is the microglia through the expression of CD39 [14]. The ATP-regulation in the blood is mediated by the red blood cells, which may regulate tissue circulation and O2 delivery by releasing the vasodilator ATP in response to hypoxia. When released extracellularly, ATP is rapidly degraded to ADP in the circulation by ectonucleotidases. Moreover, ADP acting on P2Y13 receptors on red blood cells serves as a negative feedback pathway for the inhibition of ATP release [15].
Nucleosides and nucleotides are recognized by purinergic receptors P1, P2, TLRs, and NLRs. The recognition implies that nucleosides and nucleotides are temporarily held at different concentrations to activate their respective receptors. Purinergic receptors are divided into two families: P1 and P2 receptors [1]. The G-protein coupled metabotropic P1 receptors recognize exclusively extracellular adenosine and can be subdivided into A1R, A2AR, A2BR, and A3R. The P2 receptors can be subdivided into two subtypes: non-selective ion-gated channel P2X receptors (that recognize ATP) and G-coupled P2Y receptors (that recognize ATP, ADP, UTP, UDP, and UDP-glucose) [6]. Actually, it has been described seven P2X receptors (from P2X1 to P2X7) with different affinities for ATP. The P2X7 receptor has a low affinity for ATP (requiring ≥100 mM to be activated; while others can be activated at lower concentrations) [12].
The consensus about the relationship between purinergic signaling and the immune system can be summed up by the opposing effects of ATP and adenosine. The ATP contributes to triggering the inflammatory response along with molecular patterns associated with pathogens [5]. Conversely, the adenosine nucleoside mediates anti-inflammatory and immunosuppressive actions, such as inhibiting the production of pro-inflammatory cytokines and lymphocyte proliferation [9]. However, there are other nucleotides and nucleosides modulating the immune system.
3. Effects of purinergic signaling on the innate and adaptive immune system
The eATP released from stressed, dying or infected cells bind to P2 receptors (as P2X7R) and may lead to pathogen elimination through several mechanisms: (1) host cell death; (2) inflammasome activation and IL-1β secretion; and (3) production of reactive oxygen species (ROS) and nitric oxide (NO); promoting lysosome and phagosome fusion [16].
P2X7R activation is associated with pore formation, which depends on the concentration and duration of ATP treatment [17], as well as leads to the opening of pores that allow the passage of small molecules (< 900 Da) [18] as dinucleotides or nucleosides, increasing the extracellular concentration of these purinergic ligands. Inflammasomes are multi-protein complexes assembled in the host cell in response to infection or cellular stress, leading to non-homeostatic and lytic cell death, called pyroptosis. P2X7R was shown to activate NLRP3 inflammasomes [19]; and recently, caspase-11-induced pyroptosis was shown to require pannexin-1 channels and the P2X7R activation [20]. Pyroptosis is important because of the cytokines, chemokines, and damage-associated molecular patterns (DAMPs) which are released to the extracellular compartment, and also because intracellular pathogens are exposed to extracellular immune response, thus allowing their destruction [21]. At the same time, the inflammasomes lead to the maturation and secretion of pro-inflammatory cytokines, such as IL-1b and IL-18 [21]. IL-1β affects virtually all cells and organs of the body and is one of the most important cytokines that mediate autoimmunity, infections, and degenerative diseases [22]. This cytokine has a role in the CNS as an endogenous pyrogenic agent, and it can also induce inflammation, leukocyte recruitment, and Th17 profile immune responses [23]. In addition to eATP, uridin diphosphate (UDP) is released by the cleavage of pannexin-1 channels via caspase in apoptotic cells resulting from the vesicular stomatitis virus infection. Then, the UDP-P2Y6R signaling is able to protect both cells and mice from infection through an increase in IFN-β production, in acute neurotropic infection [24].
Purinergic receptors P1 (P1R) and P2 (P2R) can be expressed simultaneously in almost all immune cells, apparently depending on their ligand concentrations in the extracellular space [25]. Therefore, eATP-P2R interactions also activate pro-inflammatory responses in immune cells [26], as we have seen in infected or dying non-immune cells.
Neutrophils, granulocytes participating in both immune systems innate and adaptative, are the first immune cells in arrived at the inflammation site, constituting the main acute inflammatory response against pathogens by both phagocytosis and the oxidative microbicidal molecules production [25]. Neutrophils are the more affected cells by the purinergic signaling, probably because they express several purinergic receptors [26]. For instance, P2Y11 receptor (P2Y11R) is responsible for the ATP-mediated differentiation and maturation of granulocytic progenitors in the bone marrow [27]. Also, the interaction between eATP-P2Y11R mediates the inhibition of neutrophil apoptosis [28] and increases the chemotactic response of neutrophils [29]. In addition to eATP, other nucleotide released by damaged cells is the uridine 5′-diphosphoglucose (UDP-glucose), which activates the P2Y14R signaling. UDP-glucose promotes chemotaxis of freshly isolated human neutrophils through P2Y14R activation [30]. Moreover, some inflammatory diseases have been related to P2Y14R activation. During pelvic inflammatory disease, in the endometria in both women and female mice, the P2Y14R and pro-inflammatory cytokines as IL-8 are up-regulated in the epithelium [31]. Then, the design of therapies to modulate mucosal immunity may be done by targeting P2Y14R [30].
Occasionally, some nucleosides are more concentrated than the ATP in the extracellular matrix. When uridine triphosphate (UTP) is more available than ATP, P2Y2 receptors (P2Y2R) may be activated by either ATP or UTP mediating several activities in the P2Y2R expressing cells. For instance, fibrotic lung disease is related to some activities mediated by P2Y2R such as the lung fibroblast’s proliferation and migration, the recruitment of neutrophils, and IL-6 secretion in the lungs [32]. By the other way, when the eATP-P2X1R signaling is activated in neutrophils and platelets, activated neutrophils are recruited to the injury site and their adherence to vessel walls together with the platelets occurred, promoting both thrombosis and fibrinogenesis [33].
In addition to neutrophils, the eosinophils, and basophils, other granulocyte cells, which are activated during parasitic infections and allergies, are also regulated by the purinergic system. The accumulation of eosinophils during lung inflammation is triggered by UTP-P2Y2R interaction that induces the expression of VCAM-1, an adhesion molecule, which in turn, induces changes in endothelial cell shape for the opening of passageways through which eosinophils migrate [34]. Moreover, P2Y2R activation by ATP in eosinophils has been reported to induce chemotaxis in allergic lung inflammation [35]. In other circumstances, when UDP have more concentrated than UTP or ATP, the UDP-P2Y6R signaling induces IgE-dependent degranulation in human basophils [36].
During infections, dendritic cells (DCs) are responsible for presenting antigens to naive T cells and activating them, making a link between the innate and adaptive immune response [37]. The ATP-P2R interaction is involved in the migration and differentiation of DCs [38]. Specifically, the eATP-P2Y11R interaction modulates the maturation of human monocyte-derived dendritic cells (MoDCs) [39]. Moreover, P2Y2R activation by ATP promotes chemotaxis of MoDCs [35]. In fact, the eATP-P2Y11R interaction mediates the migration of DCs accordingly with the DC type, although all DC populations express P2Y11R. MoDCs down-regulate the P2Y11R expression, decreasing the inhibition of migration triggered by ATP. While either interleukin-3 receptor-positive plasmacytoid DCs or CD1c + peripheral blood DCs do not inhibit their migration by ATP. Then, the possibility of a meeting between DCs and antigens may be mediated by gradients of ATP formed in and around inflamed areas. Therefore, after vaccination, the migration of DCs charged with antigens to near lymph nodes may be increased with the inhibition of P2Y11R expression. This strategy could improve the time of response after vaccination [38]. In addition, P2Y12 receptor (P2Y12R) modulates murine DCs function by ADP, including induction of intracellular Ca2+ transportation, macropinocytosis, and T-cell stimulation [40]. However, the stimulation of the P2X7R with ATP can induce cell death; such as in murine spleen-derived DCs, which increase the permeabilization and the intracellular calcium, resulting in apoptosis [41].
As reviewed, the T-cell activation by DCs can be modulated by the purinergic system. Additionally, lymphocytes (mainly T and B cells) that are characterized by expressing antigen receptors, allowing the activation of anti-microbial responses [25], also express purinergic receptors which modulates lymphocyte proliferation, differentiation, and functioning. Immature T cells pass through the thymus for differentiation, where stromal epithelial cells are in charge of both the positive and negative selection processes, which in turn defines the T cell functional profile between CD8+ or CD4+ cells [42]. In the thymus, P2X7R and P2Y2R are expressed in several cells as murine thymic epithelial cells (TECs), leading to the release of calcium from intracellular stores and increasing the permeabilization membrane [43]; possibly leading to TECs apoptosis as well as reported in DCs [41], and ending in the alteration of both T-cell differentiation and their peripheral functioning. Similarly, the eATP-P2X7R signaling leads to the opening of a transmembrane cationic channel that allows K+ efflux and Na + and Ca2+ influx and promotes cytoplasmic membrane depolarization in the phagocytic cell of the thymic reticulum [18], leading to increase permeabilization and apoptosis, and impairing of T-cell precursors proliferation.
During immune synapse, naïve T-cells release ATP throughout pannexin-1 channels, then the eATP interaction with P2X1R and P2X4R receptors regulates T-cell activation, calcium entry, and IL-2 release [44]. Also, γδ T-cells, abundant at barrier sites such as the skin, gut, lung, and reproductive tract, are activated and upregulated tumor necrosis factor-alpha (TNF-α), and interferon-γ (IFN-γ) release through the eATP-P2X4R interaction [45]. Moreover, P2X4Rs participate in the migration process of CD4+ T-cells. This migration is mediated by the chemokine stromal-derived factor-1α (SDF-1α), which triggers the T-cell polarization by the accumulation of ATP producing mitochondria near ATP-releasing pannexin-1 channels and newly expressed P2X4Rs. This set of molecules promotes both the Ca2+ influx and sustained mitochondrial ATP production required for the pseudopod protrusion and T-cell migration [46]. Conversely, exogenous activation of P2Y11R with eATP blocks T-cell trafficking [47].
Specifically, the purinergic system may modulate inflammatory severe clinical conditions like sepsis. This condition has two phases, first is the hyperinflammatory phase, which may be later restricted by the immunosuppressive phase. However, this last phase characterized by high blood levels of regulatory T cells (Tregs) is strongly associated with mortality. Tregs proliferation is controlled by P2Y12R activation in both Tregs and platelets, and P2Y12R blockade restores the immunological homeostasis. Therefore, this strategy may guide pharmacological treatment for sepsis and increase patient survival [48].
Among innate immune cells acting mainly in chronic inflammatory responses are the mononuclear phagocytes, which are in circulation as monocytes or in several tissues as macrophages, or in specific tissues as microglial cells in the brain. These phagocytes may have either a pro-inflammatory or anti-inflammatory role depending on the type of cytokines around them and express several P2 receptors [25]. For instance, the major pathway of macrophage activation is the eATP-P2Y11R signaling, which leads to cytokine release [49]. Moreover, macrophages exposed to LPS, increase the P2YR and P2X7R activation mediated by eATP, modulating the IL-1β, TNF-α, and NO production [50]. Monocyte adhesion process is also regulated by the ATP-P2R interaction [51]. For example, activated P2Y12R induces both vascular smooth muscle inflammatory changes via MCP-1 upregulation and monocyte adhesion into the vascular wall, promoting atherosclerotic lesions [52].
Microglia is the cell responsible for the immune function of the nervous system in both physiological and pathological conditions [53]. Increased P2X7R expression and its ATP-mediated activation in microglia are observed after the LPS brain challenge, leading to increased immune response associated with NO and ROS, along with reduced neuronal viability. Inhibition of this purinergic response may be a neuroprotective strategy in brain inflammatory diseases [54]. In addition, the upregulation of P2Y6, P2Y12, P2Y13, and P2Y14 receptors in spinal microglia is associated with the development of neuropathic pain [55]. In an inflammatory context, ADP acting on P2Y12R induces extension of microglia processes thereby attracting this cell to the site of ATP/ADP leaking or release. Moreover, the ADP-P2Y12R activation in microglia induces intracellular calcium accumulation, which in turn causes the increase of CC chemokine ligand 3 (CCL3) expression in the peripheral injured site and also in the spinal cord, inducing neuropathic pain. Since the inhibition of CCL3-CCR5 signaling suppresses the development of neuropathic pain, treatments based on inhibition of CCL3 expression can be promising to control this kind of inflammatory disorder [56].
The P2Y6R is also upregulated in microglia when neurons are damaged, then the UDP-P2Y6R signaling facilitates microglial phagocytosis [57]. Consistently, the brain injury caused by ischemic accidents is increased by the inhibition of both P2Y6R expression and the microglia-phagocytic activity [58]. The UDP-P2Y6R signaling is also associated with neuropathic pain and is partially explained by the induction of CCL2 production through the MAP kinases-NF-kappaB pathway in microglia [59]. CCL2 is a recruitment factor of myeloid cells to the regions with injured neurons. In the spinal cord, CCL2 released from primary afferent neurons and reactive astrocytes could contribute to either the induction or maintenance of chronic pain [60], neurodegenerative and neuroinflammatory diseases [61].
As mentioned above, in addition to purinergic receptors, other receptors are able to recognize eATP such as the NLRs and TLRs. These receptors recognize both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) (including eATP and uric acid). The relationship between these receptors and nucleotides or nucleosides, and the structure and functions of NLRs will be addressed immediately. TLRs will be explained through the case of gout disease.
The NLRs are cytoplasmic receptors and the structure has three domains: a common domain organization with a central conserved domain NOD (NACHT: NAIP, CIITA, HET-E, and TP-2), N-terminal effector domain, and C-terminal leucine-rich repeats (LRRs) [62]. The NAIP motif (neuronal apoptosis inhibitor protein) and the CIITA motif (MHC class II transcription activator) contain a distinct predicted nucleoside triphosphatase (NTPase) domain. In addition, NTPase domain in CIITA shows highly significant sequence similarity to CARD4 (pro-apoptotic protein). Therefore, the NACHT family includes both pro-apoptotic (e.g. CARD4) and anti-apoptotic (e.g. NAIP) predicted NTPases [63]. In consequence, all NLRs could modulate apoptotic process. However, either the possible apoptotic effect or the ATPase activity of the NATCH domain and the consequence on the concentration of nucleotides and derivatives in the cytoplasm must be the subject of study.
Most NLRs recognize various ligands activating inflammatory responses. These ligands come from different sources, including microbial pathogens (peptidoglycan, flagellin, viral RNA, fungal hyphae, etc.), host cells (ATPs, uric acid, etc.), and esteril activators (alum, silica, UV radiation, skin irritants, etc.). In addition, some NLRs respond to cytokines such as interferons. The activated NLRs show various functions that can be divided into four broad categories: inflammasome formation, signaling transduction, transcription activation, and autophagy [64]. Several NLRs have been used to identify inflammasomes, depending on the receptor that recognizes the PAMPs (for example, NLRP1, NLRP3, AIM2, NLRC4), while the other group of inflammasomes can be activated by cytosolic lipopolysaccharides (LPS) derived from gram-negative bacteria. The NLRP3 inflammasome can be activated by different stimuli, such as bacterial, viral, and fungal pathogens, pore-forming toxins, crystals, silica, and DAMPs (for example, eATP) [65]. The activation of the NLRP3 inflammasome requires two signals: (1) a PAMP, such as LPS, leading to transcription of NF-kB, upregulating genes encoding pro-inflammatory cytokines, chemokines, and proteins involved in the inflammasome platform; and (2) a DAMP, such as eATP, which induces inflammasome activation after ligation to the P2X7R. Once activated, these complexes promote activation of the protease caspase-1, which cleaves pro-IL-1β and pro-IL-18 into their active forms: IL-1β and IL-18 [12].
In addition to the inflammasome activation, eATP induces ROS production. ROS are highly reactive chemicals formed from O2 (such as peroxides, superoxides, and hydroxyl radicals) [66]. For instance, respiratory epithelial cells induce mitochondrial ROS in response to influenza infection. ROS induces the expression of type III interferon, a response associated with viral infection control [67]. Moreover,
Some TLRs recognize in addition to PAMPs from intracellular or extracellular pathogens, others molecules like ATP and uric acid. TLRs recognizing uric acid are involved in several metabolic and cardiovascular diseases, including gout, chronic renal tubular damage, autosomal dominant polycystic kidney disease, and cartilage degeneration. Among them, the accumulation of uric acid crystals (monosodium urate - MSU -) in the joints causes arthritis which is the base of the metabolic disease called Gout [64]. The uric acid also could cause inflammatory events by the activation of the NLRP3 inflammasome and its activation induces the IL-1β formation, which leads to the development of gouty arthropathy [69]. Moreover, when the level of uric acid is higher than 6.8 mg/dL, MSU crystals are formed and are recognized by TLRs. These TLRs then activate the NALP3 inflammasome. MSU also triggers neutrophil activation and further produces immune mediators, which lead to a pro-inflammatory response [70]. In the mice model of Gout, it was found that MSU crystals are recognized by TLR2 and TLR4 with the participation of the TLR adapter protein myeloid differentiation factor 88 (MyD88) in bone marrow-derived macrophages. After recognition by these TLRs, MSU induced the production of pro-inflammatory cytokines as IL-1β, TNF-α, keratinocyte-derived cytokine/growth-related oncogene alpha (KDC/GROα), and transforming growth factor beta1(TGF-β1). Moreover, neutrophil influx, local induction of IL-1β, and more pro-inflammatory reaction were promoted [71].
In addition, patients with hyperuricemia (high levels of uric acid in the blood) develop vascular diseases associated with the formation of aminocarbonyl radicals from excess uric acid with the concomitant oxidative effect [72]. Additionaly, metabolic and cardiovascular diseases are associated with the activation of the renin-angiotensin system (RAS) mediated by uric acid, in adipose tissue. For instance, high blood pressure and increased expression of both TLR2/4, pro-inflammatory cytokines (TNF-α and IL-6), and RAS activation in adipocytes were found in hyperuricemic rats. These high levels of cytokines and RAS components were reverted by TLR2/4 RNA silencing [73]. Proinflammatory pathways are induced by uric acid and angiotensin II-mediated by TLR4 in renal proximal tubular cells developing chronic tubular damage [74]. Moreover, TLR-2 and TLR-4 gene expressions are associated with rapid progression in autosomal dominant polycystic kidney disease (ADPKD) patients [75]. Furthermore, in human chondrocytes, the accumulation of both calcium pyrophosphate dihydrate (CPPD) and MSU crystals was associated with increased expression of TLR2 and the NO generation triggered by TLR2 signaling, inducing inflammation and cartilage deterioration. Other TLR signaling pathways producing NO release are induced by both MSU and CPPD crystals, including the Pl3K/Akt/NF-κB signaling pathway and other mediators as MyD88, IRAK1, and TRAF6 [76].
4. Downregulation of immune responses by purinergic signaling
In the lymph nodes and spleen, lymphocytes are stimulated through eATP-P2X7R interaction to promote the Th1 pro-inflammatory response [77]. However, the eATP may also play an immunosuppressive role. This mechanism occurs mainly when eATP is in low (micromolar) concentrations, increasing its affinity for P2YR, located on the surface of lymphocytes. When stimulated, P2YRs promote the downregulation in the expression and release of pro-inflammatory cytokines, promoting a protective effect against excessive tissue damage [25]. Moreover, chronic exposure of DCs to low ATP doses reduces the capacity to stimulate the Th1 response, while Th2 response is favored [78], which induces the activation of T-cells with an anti-inflammatory profile. However, micromolar levels of eATP through P2Y2R induce the mechanisms of phagocytosis and increase ROS and NO production by macrophages and neutrophils [25].
The most recognized effector of anti-inflammatory responses of the purinergic system is adenosine. Extracellular adenosine is recognized by P1 receptors (A2AR and A2BR). High concentrations of adenosine activate A2AR, inhibiting the production of pro-inflammatory cytokines by macrophages [79], and also decreasing the production of ROS and NO by neutrophils, monocytes, and macrophages. However, low concentrations of adenosine (lower than micromoles) increase phagocytosis and ROS production by activation of A1R in neutrophils [25]. Also, adenosine acts on A2AR inhibiting the production of IL-12 and TNF-α in mice liver and preventing the damage by injury [10].
A1AR and A2AR are abundantly expressed at synapses in the CNS, modulating the synaptic efficacy [80]. A1AR and A2AR receptors are also expressed in the microglia and their activation promotes anti-inflammatory and migration activities, respectively [81]. In the presence of mild alterations of CNS high amounts of ATP can be release, then the activation of P2X7R induces both activation and pro-inflammatory response by microglia, leading to surrounding neuronal death [82]. Therefore, the ATP regulation in the CNS is critical; it has been suggested that CD39 expression has an essential role in cell proliferation and growth, inflammatory processes, and triggering cellular responses from ATP-induced contribute to apoptosis and host defense [83]. Moreover,
5. Pathogens and purinergic signaling mediating immune response
Some obligated intracellular bacterial pathogens have diverse target organs. For instance,
Another bacteria controlled by eATP-triggered mechanisms is
Intracellular protozoan parasites as
During the acute toxoplasmosis, in the mice brain, occurs an increase in purines (ATP, ADP, AMP, adenosine, xanthine, hypoxanthine, and uric acid), while in chronic toxoplasmosis reduction of the same purines, except the antioxidant, uric acid, occurs [103]. Specifically, the high levels of xanthine and hypoxanthine are associated with the inhibition of the enzyme xanthine oxidase, which catalyzes the production of uric acid, reported in
Interestingly,
During acute
Interestingly, some pathogens have evolved extracellular nucleotide-hydrolyzing enzymes that mimic the ectonucleotidases expressed in the host, probably inhibiting the ATP-driven immune response [114]. For instance, the surface of
The participation of the purinergic system in the immune response and pathogenesis as a consequence of SARS-CoV-2 virus infection has also been reported. SARS-CoV-2 induces the IFN response in patients, through MDA5-mediated RNA sensing with the participation of IRF3, IRF5, and NF-κB/p65 pro-inflammatory transcription factors [117]. However, Coronaviruses can evade the MDA5 recognition by forming endoplasmic reticulum-derived membrane vesicles around their RNA [118], delaying the IFN production; and in consequence, allowing higher viral replication. Viral load is highly correlated with the levels of IFNs and TNF-α, suggesting that viral load may drive high cytokine production [119]. Increased levels of TNF-α during inflammation induce ATP release via pannexin-1 channels [120]. ATP exportation out of the cell implies a deficit of intracellular ATP available for the ATP-dependent enzymes in the JAK–STAT pathway induced by IFN-I, limiting the cytokine expression and T helper cell activation [121].
At the same time, a pro-inflammatory immune response is initiated by the increase in the extracellular ATP and ADP levels in the microenvironment of immune cells activating the P2XRs and P2YRs [122]. The eATP-P2X7R signaling activation is a key process in the hyper inflammation resulting from the severe pro-inflammatory immune response against SARS-CoV-2 [123]. High levels of eATP are accompanied by the desensitization of all P1 and P2 purinergic receptors, except P2X7R, inducing more hyper inflammation [124], the worst scenario for a COVID-19 patient.
Shortly after the inflammatory explosion or simultaneously, the eATP concentration could decrease by the CD39-mediated transformation into eADP and eAMP, while adenosine quickly increases by the CD73-mediated eAMP conversion [125]. Then, immunosuppressive responses are activated by the adenosine excess in interaction with their A2AR and A2BR, including inhibition of macrophages and lymphocytes [10].
Moreover, increased eADP levels promote platelet activation and intravascular thrombosis mediated by P2YRs [126], and COVID-19 patients with pneumonia frequently developed microvascular thrombosis in their lungs [127]. In summary, the degree of involvement of purinergic receptors and their ligands in the response to SARS-CoV-2 virus infection may partially explain, the presence of asymptomatic infected people and the variation in the severity among the COVID-19 patients.
6. Perspectives
During inflammation, macrophages, NK cells, and some lymphocytes activities are impaired by the interaction of their adenosine receptors and the high extracellular levels of adenosine [10]. Therefore, the factors involved in extracellular adenosine production may be used in anti-inflammatory strategies, including the ectonucleotidases CD39 which degrades ATP into AMP, and the ectonucleotidase CD73 which converts AMP into adenosine. Following this rationale, several monoclonal antibodies (mAb) have been developed using CD73, CD39, and A2AR receptors as a target [128]. For instance, a humanized anti-CD39 mAb prevents the ATP-ADP conversion. Moreover, the enhancement of T cells and NK cells function was found, when CD39 was blocked by either antibodies or inhibitors such as POM-1; aside from increased T cell proliferation by the lack of suppression exerted by Treg cells [129].
Moreover, the prevention of AMP to adenosine conversion is also achieved using the mAb anti-CD73 which leads to its internalization [130]. As consequence, the adenosine low levels can not inhibit lymphocytes, therefore CD8 and macrophages activities are enhanced, while both myeloid suppressor cells and Treg lymphocytes are inhibited [128]. Lymphocyte proliferation is also promoted with the administration of an A2AR antagonist in two ways, removing checkpoints on both CD4+ FoxP3+ Tregs and CD8+ effector T cells development, and inhibiting the expression of the programmed death-1 receptor (PD-1) in draining lymph nodes [131]. Some of these drugs have been used as anti-cancer therapies, nevertheless, they have a potential action in many diseases based on immunosuppressive mechanisms.
On the other hand, antagonists of P2X7R as lidocaine can disrupt hyperinflammation, leading to the activation of anti-inflammatory responses. For instance, the clonal expansion of Tregs in lymph nodes is promoted by the P2X7Rs-mediated inhibition of the immune cells in the lymphatic system. Later, the Tregs control the hyperinflammation throughout their anti-inflammatory mechanisms [16]. Also, since eATP-P2Y11R signaling is highly activated in macrophages, P2Y11R antagonists maybe they can be used for the treatment of inflammatory diseases [40]. These strategies may constitute immunotherapy with promising results for inflammatory-based diseases, such as severe forms of various viral or bacterial infections, or even autoimmune diseases.
7. Conclusion
PX and PY receptors are involved in the inflammasome activation, apoptosis induction, oxidant production and activation of several immune cells, mechanisms that can control the infection of several pathogens. Conversely, adenosine is generally associated with the downregulation of inflammation. However, the effects triggered by eATP and nucleosides and their respective purinergic receptors in infected cells, depend on several aspects. These include first, the ability of the receptor expression by infected cells; second, the mechanisms to maintain the balance of nucleotide and nucleoside concentrations in the extracellular environment; and third, the survival strategies of specific pathogens.
The purinergic signaling can modulate infections by different intracellular pathogens, including viruses, bacteria, and parasites, and mediates inflammatory processes in metabolic, cardiovascular, and cancer diseases. For this reason, this knowledge field represents an important focus for future research regarding the survival and elimination of different pathogens and the maintenance of the homeostasis of the diseases related to hyper-inflammation.
Acknowledgments
Post-doctoral Fellowship of Research Support Foundation of the State of Rio de Janeiro–FAPERJ—Health Research Networks Program in the State of Rio de Janeiro—2019, Brazil. Processo E-26/ 202.139/2020.
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