UDP-glucose sensing P2Y14R: A novel target for inflammation

Uridine 5'-diphosphoglucose (UDP-G) as a preferential agonist, but also other UDP-sugars, such as UDP galactose, function as extracellular signaling molecules under conditions of cell injury and apoptosis. Consequently, UDP-G is regarded to function as a damage-associated molecular pattern (DAMP), regulating immune responses. UDP-G promotes neutrophil recruitment, leading to the release of pro-inflammatory chemokines. As a potent endogenous agonist with the highest affinity for the P2Y14 receptor (R), it accomplishes an exclusive relationship between P2Y14Rs in regulating inflammation via cyclic adenosine monophosphate (cAMP), nod-like receptor protein 3 (NLRP3) inflammasome, mitogen-activated protein kinases (MAPKs), and signal transducer and activator of transcription 1 (STAT1) pathways. In this review, we initially present a brief introduction into the expression and function of P2Y14Rs in combination with UDP-G. Subsequently, we summarize emerging roles of UDP-G/P2Y14R signaling pathways that modulate inflammatory responses in diverse systems, and discuss the underlying mechanisms of P2Y14R activation in inflammation-related diseases. Moreover, we also refer to the applications as well as effects of novel agonists/antagonists of P2Y14Rs in inflammatory conditions. In conclusion, due to the role of the P2Y14R in the immune system and inflammatory pathways, it may represent a novel target for anti-inflammatory therapy.


Introduction
The P2Y 14 R is a G protein-coupled P2Y receptor (R) that was formerly known as GPR105 or uridine 5′-diphosphoglucose (UDP-G) receptor. Originally, it was characterized as an orphan receptor, named KIAA0001 and has been shown to be activated by extracellular UDP-G. There is plenty of evidence that UDP does bind to the P2Y 14 R and seems to act as a partial agonist (Carter et al., 2009a;Gao et al., 2010a). The P2Y 14 R is known as the UDP-glucose receptor -but this is not an exclusive association, depending on nucleotide concentration (Ko et al., 2009). There was an earlier paper reporting that UDP acts as a P2Y 14 R antagonist (Fricks et al., 2008), but that was corrected in a later publication of the same group (Carter et al., 2009b). UDP-G is utilized in nucleotide sugar metabolism as an activated form of glucose, playing key biochemical roles in multiple metabolic pathways, including glycosyl donors for glycosylation reactions and biosynthesis of polysaccharides such as glycogen, lipopolysaccharides, and glycosphingolipids (Rademacher et al., 1988;Schulman and Kennedy, 1977;Ralevic, 2015). As a UDP-sugar, UDP-G is essential for glycogen metabolism that controls macrophage-related inflammation. Macrophages are closely associated with the formation of the nod-like receptor protein 3 (NLRP3) inflammasome, which subsequently promotes the release of inflammatory factors (Ren et al., 2021;Chen et al., 2021). When macrophages are activated, oxidative phosphorylation rapidly switches to glycolysis. Intriguingly, UDP-G generated during glycolysis may reach the extracellular space and, then, activates P2Y 14 Rs, resulting in the modulation of an important inflammatory transcription factor, signal transducer and activator of transcription 1 (STAT1) . UDP-G also participates in the purinergic signaling pathway, which is essential for cell-to-cell communication, including immunity and inflammation. One prominent feature of the P2Y 14 R is its coupling to P2Y 14 Rs are ubiquitously distributed in both humans and rodents. Placenta, adipose tissue, stomach, and intestine were shown to exhibit the highest expression of the P2Y 14 Rs in humans, whereas in the brain, lung, heart, spleen, and bone marrow, they were moderately expressed (Chambers et al., 2000)(). Interestingly, although originally the P2Y 14 R expression in the liver has been reported to be low, a recent study identified highly enriched P2Y 14 Rs in hepatic stellate cells (HPSCs), the main fibrogenic cell type of the liver (Mederacke et al., 2022). The rat (r) P2Y 14 R, as a presumed rat ortholog with 80% amino acid similarity to the first 293 amino acids of human (h)P2Y 14 R, was isolated from the ventral tegmentum (Freeman et al., 2001). This provided the possibility to utilize rodents as a model to explore the function of the P2Y 14 R, since its distribution is very consistent with findings obtained with its human ortholog (Freeman et al., 2001;Charlton et al., 1997).
Since the P2Y 14 R has been recognized for its distinct novel pharmacology, increasing research has been conducted to elucidate its essential physiological roles by mediating extracellular signaling. Emerging evidence demonstrates that the P2Y 14 R plays a key role in multiple functions including hematopoiesis, metabolism, analgesia, and most significantly, immunomodulation, which primarily suggests a role in inflammation. Both human and rat P2Y 14 Rs are widely expressed in

AC
Adenylyl cyclase ASC Apoptosis-associated speck-like protein containing a CARD AKI Acute kidney injury ATGL Adipose triglyceride lipase ARDS Acute respiratory distress syndrome BMEC Blood-brain barrier endothelial cell βENaC-Tg Transgenic mice overexpressing the β-subunit of the epithelial sodium channel ENaC encoded by the Scnn1b gene cAMP Cyclic adenosine monophosphate CCL2 C-C motif chemokine ligand 2 COPD Chronic obstructive pulmonary disease Ca3 Carbonic  (continued on next page) the brain and are specifically localized in glial cells, notably astrocytes. In the spinal cord, an immune cell that could not be clearly identified, also expresses P2Y 14 Rs; this cell type was inferred to be microglia rather than astrocyte (Kobayashi et al., 2006). Additionally, the P2Y 14 R is notably expressed in peripheral immune cells such as lymphocytes, megakaryocytes, neutrophils and macrophages, which directly participate in inflammatory responses.

The UDP-G/P2Y 14 R signaling pathway is a critical proinflammatory mediator in multiple systems
In recent years, accumulating evidence has shown that the P2Y 14 R functions as a critical and extensive proinflammatory mediator in various organs and tissues, including the liver, kidney, lung, blood, joint, epididymis, and trigeminal ganglion, etc (see Table 1). When stimulated by lipopolysaccharide (LPS), an immunologic challenge that can induce inflammation, the P2Y 14 R expression was significantly up-regulated (Moore et al., 2003). The known immunological functions of P2YRs have been extended to stem cells as a result of the discovery that P2Y 14 Rs mediate primitive cell responses to certain hematopoietic microenvironments, suggesting that such P2Y-like receptors may be involved in responses to injury at the most fundamental level of healing, which is an important function of stem cells (Lee et al., 2003).
Restraining P2Y 14 Rs and their downstream signaling pathways, therefore, is a promising approach to block pro-inflammatory responses, which further exert considerable beneficial effects on inflammationrelated disorders. The cAMP-NLRP3 inflammasome pathway is one of the most significant signaling mechanisms involved in the UDP-G/ P2Y 14 R-mediated inflammation. Some of the second messenger systems coupled to P2Y 14 R activation are visualized in Fig. 1. However, within Vasectomy-induced spermatozoa congestion may lead to an inflammation-prone local environment, characterized by potential activation of P2Y14Rs and recruitment of immune cells in the epididymis. Belardin et al., 2022 For all abbreviations see the List of Abbreviation.

Fig. 1.
The P2Y14 signaling pathway. UDP glucose binds to the P2Y14R to modulate the accumulation of cAMP, the inhibition of which negatively regulates NLRP3 inflammasome activation and the downstream maturation of IL-18 and IL-1β, as well as Gasdermin D-dominated pore formation for the cell membrane-involved pyroptotic cell death. Meanwhile, the P2Y14R activates MAPK (which has three subtypes namely JNK, ERK and p38) and STAT1 signaling transduction via modulating Gi/o coupling-involved p-Raf-1/p-MEK/p65NF-κB route. The activation of the above-described P2Y14R-dependent pathways lead to the release of diverse cytokines and chemokines.
the past decade, a range of further signaling pathways have been recognized which also may participate in the P2Y 14 R-mediated effects. For example, during weak Gi/o stimulation, the dephosphorylation of phosphatidylinositol 4,5-bisphosphate (PIP2) occurs, which further facilitates canonical transient receptor potential 4β (TRPC4β) activation (Thakur et al., 2016). β-arrestin 1/2 are essential for the efficient activation of the Gi/o-mediated MAPK signaling (Shiraki and Shimizu, 2023), and Gi/o-mediated signaling in turn is modulated by regulator of G protein signaling (RGS20) (Zhang and Sjögren, 2023). As discussed above, the P2Y 14 R is highly expressed in immune cells, allowing for direct modulation of immune responses (Scrivens and Dickenson, 2005;Gao et al., 2010b). When injured or exposed to mechanical stress, damaged cells release nucleotides including ATP/UT-P/UDP and UDP-G, which trigger inflammatory transduction. UDP-G is a highly stable proinflammatory mediator, and as a physiologically important agonist of P2Y 14 R. Due to the fact that UDP-G serves as an extracellular signaling molecule, it has been considered a danger signal, one of the DAMP molecules (Lazarowski and Harden, 2015;Lazarowski et al., 2003). The upregulation of P2Y 14 R mRNA expression by lipopolysaccharide is another indicator of its inflammatory function (Moore et al., 2003;Arase et al., 2009).

Antagonism of P2Y 14 R may be a promising treatment for pulmonary inflammation
In 2005, it was revealed for the first time that P2Y 14 R mRNA was expressed in human lung epithelial cells. Furthermore, it was found that Ca 2+ -transients and the release of the proinflammatory cytokine interleukin (IL)-8 could be stimulated by UDP-G. Although it has not been reported that the P2Y 14 R directly modulates immunological responses, these findings provide support for the hypothesis that the P2Y 14 R may play a significant role in inflammatory regulation owing to its unique activation by UDP-G (see also above; (Müller et al., 2005)). In a subsequent study, the P2Y 14 R antagonist 4-(piperidin-4-yl)-phenyl)-7-(4-(trifluoromethyl)-phenyl-2-naphthoic acid (PPTN) was demonstrated to abolish the UDP-G-induced enhancement of neutrophil lung recruitment. Furthermore, application of PPTN to βENaC-Tg mice (a transgenic mice overexpressing the β-subunit of the epithelial sodium channel ENaC encoded by the Scnn1b gene) attenuated lung neutrophil inflammation (Sesma et al., 2016;Mall et al., 2004). Lung neutrophil inflammation not only results in neutrophil recruitment but also raises the risk of peripheral thrombocytopenia. PPTN was also demonstrated to reduce the risk of lung inflammation induced by LPS (Amison et al., 2017).
In a more recent study, P2Y 14 R-deficient mice exhibited a significant reduction of airway eosinophilic infiltration/inflammation, and PPTN treatment likewise decreased airway eosinophilia, despite the absence of evidence indicating that the interaction of UDP-G with P2Y 14 Rs increases allergic sensitization via the airways. These results show that antagonism of P2Y 14 Rs may be a promising treatment for pulmonary inflammation, reducing lung damage, asthma, and pulmonary peripheral thrombocytopenia . Intriguingly, in contrast to earlier studies that suggested that P2Y 14 Rs act as proinflammatory mediators, patients with higher P2Y 14 R expression had a better prognosis than those with lower expression in patients after surgery of lung adenocarcinoma (LUAD), indicating that P2Y 14 Rs may be linked to LUAD immune invasion and play a significant role in preventing tumor cell immune escape within the LUAD microenvironment (Xu et al., 2022).

UDP-G/P2Y 14 receptor axis activation is to blame for renal injury and ischemic acute kidney injury
It has been also discovered that kidney tissue expresses P2Y 14 R mRNA (Chambers et al., 2000)(). P2Y 14 Rs were also reported to be significantly and specifically expressed in collecting duct intercalated (IC) cells. In addition, blocking P2Y 14 Rs with PPTN could prevent the increase of pro-inflammatory chemokines via the mitogen-activated extracellular signal-regulated kinase (MEK)1/2-extracellular signal-regulated kinase (ERK)1/2 pathway in ICs and in Madin-Daby canine kidney cell (MDCK)-C11-lines), induced by UDP-G stimulation. Since P2Y 14 R expression was not detectable in other renal epithelial cells, ICs therefore could be identified as a novel sensor and mediator of inflammation in the kidney via P2Y 14 Rs Azroyan et al., 2015).
These findings shed light on ischemic acute kidney injury (AKI), a potentially fatal medical complication associated with inflammation. According to a recent study, ICs rapidly adopt a proinflammatory phenotype following murine renal ischemia reperfusion injury (IRI). Moreover, by inhibiting P2Y 14 Rs that are specifically expressed on ICs during the early phase of this disease, ablation of the gene encoding the P2Y 14 R or inhibiting P2Y 14 Rs on the apical membrane of ICs could both attenuate IC-specific upregulation of proinflammatory chemokines (including Cxcl1, Cxcl2, Ccl2, Il1b) induced by IRI. P2Y 14 Rs themselves, together with a number of proinflammatory chemokines, were increased 2 h after IRI, in line with the previous observation that UDP-G injection could induce renal neutrophil infiltration in healthy mice. In addition, this work identified a UDP-G/P2Y 14 R signaling pathway that caused early renal inflammation, leading to kidney dysfunction and proximal tubule damage after renal injury. By inhibiting P2Y 14 Rs, neutrophil and monocyte renal infiltration, kidney dysfunction, and proximal tubule damage were reversed, indicating that the UDP-G/P2Y 14 R axis is a promising target for regulating inflammatory responses in the kidney, preventing and even attenuating ischemic acute kidney injury (Breton and Brown, 2018;Battistone et al., 2020).

P2Y 14 receptors in hematopoetic stem cell regulation, neutrophil recruitment and platelet activation, as well as in thrombo-inflammation
The cardiovascular and lymphatic systems are two general divisions of the circulatory system. The lymphatic system is composed of lymph, lymphatic vessels, lymph nodes, lymphoid tissues, and lymphoid organs, whereas the cardiovascular system consists of blood, the heart, and blood vessels. The spleen is the largest lymphoid organ, and the bone marrow, tonsil, and thymus are also central lymphoid organs, serving a key role in immune functioning. The P2Y 14 R is characterized by wide distribution in the heart, spleen, and bone marrow, as well as in immune cells such as T-lymphocytes, indicating that it plays a crucial role in the circulatory system immune responses (Chambers et al., 2000;Scrivens and Dickenson, 2005).
As previously mentioned, the placenta, a rich source of hematopoietic stem cells (HSCs), expresses the highest levels of P2Y 14 Rs. HSCs differentiate into immune cells including red blood cells, platelets, neutrophils, eosinophils, basophils, monocytes, T and B lymphocytes, natural killer cells, and dendritic cells, and they exhibit remarkable motility in response to certain signals, departing and re-entering the endosteal bone-marrow HSC niche. Therefore, they serve a key role in the circulatory system (Wilson and Trumpp, 2006;Blank et al., 2008) in both adult and fetal samples. A subset of primitive HSCs and hematopoietic progenitor cells in human bone marrow, express P2Y 14 Rs. Furthermore, P2Y 14 Rs can also regulate the regeneration characteristics of HSCs, responding to specific hematopoietic microenvironments (Lee et al., 2003). P2Y 14 R knockout leads to decreased HSC capacity of responding to diverse stress factors including radiation stress, aging, sequential exposure to chemotherapy, and serial bone marrow transplantation. The aforementioned forms of stress accelerated senescence in P2Y 14 R-deficient mice, which lose more bone-marrow cells and develop hypersensitivity to hematological stress when compared to wild-type mice (Cho et al., 2014). These findings strongly reinforce the importance of P2Y 14 Rs in HSC.
Neutrophils are a part of the innate immune system, one of the factors regulating the outcomes of HSC differentiation. When infected or injured, neutrophil recruitment occurs, infiltrating into various epithelial tissues, including the lung and kidney (Sesma et al., 2016;Azroyan et al., 2015). However, high levels of neutrophils also lead to an inflammatory state due to the cytotoxic damage causing massive release of cytokines, such as IL-1 and tumor necrosis factor (TNF), leading to cytokine storm. Moreover, the continuous release of further proinflammatory factors results in thrombosis due to thrombotic/fibrinolytic alterations (Lintzmaier Petiz et al., 2021;Klok et al., 2020). In addition to the previously described modulation in progenitor cell function, P2Y 14 Rs are crucial participants in neutrophil recruitment and chemotaxis, which is accomplished by regulating platelet activation. Platelet activation has been described in patients with various pulmonary diseases including chronic obstructive pulmonary disease (COPD), acute lung injury and infectious diseases (Twaddell et al., 2019). Platelet activation is always present in various inflammatory disorders and has an important impact on leukocyte recruitment. The stimulation of platelets with P2Y 14 R agonists (UDP-G, MRS2690) resulted in platelet-dependent neutrophil chemotaxis, whilst antagonism of P2Y 14 Rs with PPTN decreased pulmonary neutrophil recruitment and reversed the incidence of peripheral thrombocytopenia induced by LPS (Amison et al., 2017). Collectively, these findings revealed the role of P2Y 14 Rs in neutrophil recruitment and platelet activation.
Furthermore, it has been demonstrated that P2Y 14 R antagonism inhibits carbonic anhydrase (Ca3)-induced mast cell degranulation, which contributes to thrombo-inflammation by releasing histamine, serine proteases, and great amounts of heparin (Gao et al., 2013;Mastellos et al., 2020). During inflammatory processes, neutrophils release extracellular neutrophil traps carrying the Ca3 protein, which in turn activates mast cells. The P2Y 14 R antagonist PPTN inhibits the enhanced C3a-induced β-hexosaminidase release induced by both UDP-G and MRS2690 (Gao et al., 2013;Liu et al., 2022). Antagonism of P2Y 14 Rs may thus limit thrombo-inflammation in two ways upstream: (1) by suppressing platelet and neutrophil activation and, consequently, C3a release, and (2) by inhibiting mast cell degranulation, thereby reducing heparin release. These findings indicate a potential novel target for cytokine storm-related thrombo-inflammatory disorders induced by infection, such as the two highly associated fatal syndromes, acute respiratory distress syndrome (ARDS) and AKI shown in coronavirus disease 2019 (COVID-19) (Lintzmaier Petiz et al., 2021). Recent evidence suggests that P2Y 14 Rs may be promising targets for diabetic cardiac disorders. The levels of P2Y 14 R expression and IL-1β significantly increased in diabetic rats. However, they were reversed after treatment with P2Y 14 R shRNA, and abnormalities in blood pressure ND heart rate variability have been normalized .

UDP-G/P2Y 14 R axis linking glial cells to attenuate the inflammatory phenotype via ERK, p38, STAT1 pathways in the nervous system
The P2Y 14 R is widely distributed throughout the brain and spinal cord (Chambers et al., 2000) (). In response to an immunological challenge induced by LPS, the P2Y 14 R mRNA expression in the rat brain is up-regulated, which agrees with a previous study reporting that VTR15-20 mRNA expression is significantly up-regulated in rat brain and spleen following LPS stimulation (Charlton et al., 1997). More importantly, in addition to the description of its function in response to immune stimulation, the P2Y 14 R has been shown to specifically co-localize with glial fibrillary acidic protein (GFAP)-expressing astrocytes (Moore et al., 2003). In a further investigation, thrombin and the protease-activating receptor-1 (PAR1) agonistic peptide TFLLRNPNDK which is highly associated with inflammation and astrogliosis, induced Ca 2+ -dependent release of UDP-G from astrocytoma cells (Radulovic et al., 2016;Friebel et al., 2021). Given the presence of P2Y 14 Rs in astrocytes, UDP-G may play a significant role in extracellular signaling in addition to its well-established function in metabolic processes. These data also support the significance of the UDP-G/P2Y 14 R axis in brain immunoregulation (Kreda et al., 2008).
Thus, being expressed on neurons, P2Y 14 Rs seem to exert their actions through glial cells. In addition to astrocytes, emerging data suggest that P2Y 14 Rs may have a close interaction with microglia in the brain. In contrast to prior studies, in which P2Y14R antagonists ameliorated inflammation, specific P2Y 14 R activation with UDP-G inhibited microglial IL-6 production and tumor cell proliferation, suggesting the supportive role of P2Y 14 Rs in anti-inflammation and ultimately glioma regression (Curet and Watters, 2018). Additional recent studies also indicate that P2Y 14 Rs may contribute to neuropathic and inflammatory pain in the nervous system. Following inflammatory stimulation in the trigeminal cervical complex in a rodent model of migraine, P2Y 14 R expression, microglial activation, and ERK1/2 phosphorylation in microglia increased dramatically, whilst PPTN reversed the effects caused by repeated dural stimulation (Zhu et al., 2021). These results agree with those of an in vivo study showing that PPTN significantly reversed chronic neuropathic pain following nerve injury (Mufti et al., 2020). It is also consistent with the involvement of P2Y 14 Rs in satellite glial cell activation in the trigeminal ganglia following nerve injury and inflammatory conditions. PPTN abolished the enhanced release of IL-1β and chemokine CCL2 via ERK and p38 pathways (Lin et al., 2019).
Another study also documented that P2Y 14 Rs are located upstream of the ERK1/2 signaling pathway, since their expression was highly associated with the phosphorylation of ERK1/2, leading to the production of proinflammatory cytokines such as IL-8 and IL-1. The up-regulated P2Y 14 Rs and subsequent inflammatory responses induced by cerebral ischemia were both down-regulated by geniposide, a compound with beneficial effect in ischemic brain injury (Li et al., 2016). In two recent studies, P2Y 14 R shRNA has been applied to further support the previous findings. In both diabetic cardiac autonomic neuropathy (DCAN) and diabetic neuropathic pain (DNP), P2Y 14 R shRNA has been shown to relieve the inflammatory responses, and therefore, to alleviate the symptoms of these illnesses. P2Y 14 R shRNA not only reversed the elevated expression of P2Y 14 Rs and IL-β, but also relieved DCAN by increasing expression of nuclear factor erythroid 2-related factor 2 and glutathione peroxidase 4, which are important for maintaining homeostasis and cells survival and for the reduction of reactive oxygen species (ROS) in superior cervical ganglia .
UC.25+ is a long non-coding RNA expressed at increased levels in nervous tissue of a rat model of type-2 diabetes. In DNP, long noncoding RNA (lncRNA-UC.25+) shRNA reduced the P2Y 14 Rs expression in DNP rats, and in addition restrained the activation of microglia, which is important to attenuate inflammatory responses via the p38 pathway. Moreover, this study demonstrated that UC.25+ shRNA may alleviate DNP in rats by regulating P2Y 14 R functions in spinal microglia via STAT1 (Wu et al., 2022). Intriguingly, this regulation appears to be bidirectional. As evidence indicates, knockdown of STAT1 alleviates interferon (IFN)-γ/LPS-induced inflammatory gene expression . The suppression of the enzyme-coding genes Pgm1, Ugp2, and Pygl down-regulates STAT1 expression, which is surprisingly reversed by exogenous UDP-G administration. Nevertheless, despite the fact that P2Y 14 R siRNA also causes a decrease in STAT1 expression, UDP-G failed to rescue STAT1 expression in macrophages lacking P2Y 14 Rs. In addition, retinoic acid-β (RARβ), one of the transcription factors believed to promote STAT1 expression (Kolla et al., 1997;Shang et al., 1999), has been down-regulated by P2Y 14 R inhibition, while P2Y 14 R activation has the opposite impact on RARβ expression. These findings indicate that UDP-G/P2Y 14 R-RARβ axis is crucial for STAT1 regulation. In addition to regulating STAT1 expression, UDP-G is also able to restore STAT1 phosphorylation following disruption of glycogenolysis by Pygl siRNA, which inhibits STAT1 activation. By inhibiting phosphatase T-cell protein tyrosine phosphatase 45, an important enzyme that dephosphorylates STAT1 Pelzel et al., 2013;Shields et al., 2008), UDP-G/P2Y 14 R signaling enhances STAT1 phosphorylation. Collectively, the UDP-G/P2Y 14 R pathway closely regulates STAT1 in both expression and activity, and vice versa, STAT1 in turn participates in P2Y 14 R regulation.

Inhibition of P2Y 14 Rs alleviates insulin resistance-related inflammation and lipolysis in obesity and type-2 diabetes
The activity of the immune system is altered in obesity and type-2 diabetes, and chronic inflammation is increasingly being observed in a range of long-term diseases including those previously described, in which insulin resistance is a prominent metabolic hallmark (Donath and Shoelson, 2011;Spranger et al., 2003). It has been widely recognized that inflammation is directly associated with insulin resistance, and by inhibiting inflammation via NF-κB and JNK pathways or by cytokines, such as IL-1, alleviates the inflammation-related insulin resistance (Shi et al., 2006;Saltiel and Olefsky, 2017). In P2Y 14 R knockout mice, liver macrophage infiltration and inflammation decreased, whereas insulin-stimulated Akt phosphorylation was enhanced in liver, muscle, and adipose tissue. In addition, UPD-G levels were higher in obese mice plasma than in lean mice plasma, and most importantly, insulin sensitivity improved in mice kept on a high-fat diet, in parallel with the deletion of P2Y 14 Rs. These findings indicate that P2Y 14 Rs may mediate a high-fat diet-induced insulin resistance via inhibition of macrophage recruitment and tissue inflammation (Xu et al., 2012).
A recent study investigated adipocyte P2Y 14 Rs to figure out the role of P2Y 14 Rs in the regulation of whole-body glucose and lipid homeostasis. Initially, the study revealed a positive correlation between P2Y 14 expression level and obesity in humans, with a dramatic increase in human adipose tissue in obese individuals compared to lean individuals. Then, it was demonstrated that adipocyte-specific P2Y 14 R KO mice exhibited improved glucose tolerance and insulin sensitivity, as well as decreased expression of inflammatory markers such as IL-6, TNF-α, and macrophage inhibitory protein-1 (MIP1). Furthermore, by activating P2Y 14 Rs with MRS2905, lipolysis was suppressed in mature adipocytes, and this effect was sensitive to inhibition of P2Y 14 Rs with PPTN. These findings further indicate that the P2Y 14 R might be a promising target for the therapy of obesity and type-2 diabetes via regulating inflammation and lipolysis (Jain et al., 2021).

The P2Y 14 R is a key mediator linking ERK to profibrogenic pathway in the liver
Fibrosis is a leading cause of mortality in chronic liver diseases, unfortunately, no effective treatment exists (Angulo et al., 2015). Thus, it is an urgent task to target the link between cell death and fibrosis in the liver. The P2Y 14 R has been identified to be highly expressed in hepatic stellate cells (HSCs), the main fibrogenic cell type of the liver. Moreover, P2Y 14 Rs promote fibrogenesis with increased expression in fibrotic liver but decreased expression on a per-cell level in activated HSCs from chemokine CCl4-induced chronic liver injury, indicating that P2Y 14 Rs may drive negative feedback in chronic liver injury. In addition, UDP-G promotes ERK and Yes-associated protein (YAP) signaling in HSCs. ERK is a potent profibrogenic pathway in HSCs that is closely associated with inflammation (Foglia et al., 2019), and ERK phosphorylation was eliminated in P2Y 14 R-deficient HSCs. More importantly, both global and HSC-selective P2Y 14 R deficiency in multiple mouse models of liver injury attenuated liver fibrosis, indicating that antagonism of P2Y 14 Rs may be a novel target for counteracting the lethal outcomes of chronic liver fibrosisMederacke et al., 2022 ().
2.7. The P2Y 14 R/cAMP pathway represents a highly prospective therapeutic target for acute gouty arthritis Gout is a type of inflammatory arthritis: it has been classified as an autoinflammatory disease caused by deposition of monosodium urate (MSU) crystals, and is characterized by swelling of joints and inflammation symptoms accompanied with acute pain (Dalbeth et al., 2021). The formation of MSU crystals leads to activation of NLRP3 inflammasome, accompanied by recruitment of monocytes and neutrophils, releasing IL-1β, which has a significant role in the initiation of the gout flare (Martinon, 2010). As mentioned already repeatedly, the P2Y 14 R, initiates a signal transduction pathway via a Gi/o coupled protein to inhibit AC-mediated cAMP production that enables the activation of the NLRP3 inflammasome (Scrivens and Dickenson, 2005;Lee et al., 2012;Chen et al., 2019). Recent research indicates that P2Y 14 R deficiency attenuates MSU-induced histopathological alterations and dramatically suppresses NLRP3 inflammasome activation, followed by inhibition of pyroptotic cell death, characterized by positivity for caspase-1. Based on previous research regarding the interaction between cAMP and the NLRP3 inflammasome, the adenylate cyclase activator forskolin has been utilized, and as a result, the enhanced cAMP levels alleviated the MSU-induced activation process in gout via the NLRP3 signaling pathway; in contrast the adenylate cyclase inhibitor SQ22536 reversed the protective effect of P2Y 14 R deficiency . Consistent with this study, novel antagonists of P2Y 14 Rs have also been demonstrated to block NLRP3 inflammasome activation through P2Y 14 R-cAMP pathways, therefore having a therapeutic impact on acute gouty arthritis. Compound 8, 3-amide-5-aryl benzoic acid derivatives (compound 11m), and 4′-(1-acetylpiperidin-4-yl)-5-(4methylben zamido)-[1, 1′-biphenyl]-3-carboxylic acid (HQL6) are two new P2Y 14 R antagonists that have been applied successfully in gouty arthritis with low half maximal inhibitory concentration (IC 50 ) values Lu et al., 2021;Zhou et al., 2023).

The P2Y 14 R is a pro-inflammatory receptor in the reproductive system
As described above, P2Y 14 Rs play a key role in immune regulation, and cause increased secretion of CXCL8/IL-8 in human epithelial cells (Müller et al., 2005). Accordingly, P2Y 14 Rs have been also detected in the epithelium of the human and mouse female reproductive tract. It has been proposed that during menstruation or inflammatory conditions, such as endometriosis, the P2Y 14 R is activated, releasing IL-8. The injection of UDP-G stimulates neutrophil recruitment and production of IL-8, while blockade of P2Y 14 Rs alleviates inflammatory responses induced by LPS-or UDP-G application in the mouse uterus (Arase et al., 2009). More recently, the P2Y 14 R has been identified as a pro-inflammatory receptor in the human epididymis. Compared with non-vasectomized men, the P2RY 14 R mRNA expression in the corpus and cauda testis increased following vasectomy. This was accompanied by the appearance of numerous CD45 + leukocytes and increased CXCL10 mRNA concentrations in the cauda, as well as decreased CCL2 mRNA in the corpus. Despite the absence of a change in IL-8 and IL-1 mRNA, the results imply that P2Y 14 R activation may contribute to an inflamed-prone local environment driven by vasectomy-induced spermatozoa congestion in the epididymis via recruitment of immune cells (Belardin et al., 2022).

Conclusion
Owing to the specific interaction between UDP-G and P2Y 14 Rs, the notion of a UDP-G/P2Y 14 R axis is increasingly well recognized. UDP-G levels are highly associated with the recruitment of immune cells and glycogen metabolism, that are widely involved in immune regulation and inflammatory responses; therefore, the UDP-G/P2Y 14 R axis presents a prospective broad anti-inflammatory platform via diverse approaches including the cAMP-NLRP3, MAPKs, and STAT1 pathways. In addition to the inflammation-related pathways, however, a greater understanding of the interaction between glial cells and P2Y 14 Rs is required, since P2Y 14 Rs appear to exert their influence through glial cells in the central neuron system. This may lead to the development of more effective strategies for the healing of neurological diseases presently without effective therapies. Considerable efforts have been undertaken to reveal that antagonism of the P2Y 14 R ameliorates inflammatory diseases (see Table 2). Being a potent antagonist of the P2Y 14 R, PPTN has been used to treat a variety of inflammatory conditions, although in most cases these were acute inflammatory reactions. Due to the role of chronic inflammation in intractable disorders such as Alzheimer's disease, type-2 diabetes, chronic pain, etc., future research should focus on the development of therapeutic applications for chronic inflammatory diseases. Unfortunately, no P2Y 14 R antagonist has passed hitherto clinical trials, whereas the P2X7R, the most well-known P2 receptor involved in inflammation, has already been under repeated clinical investigation (Di Virgilio et al., 2017). Newly synthesized P2Y 14 R antagonists with enhanced solubility and bioavailability have been evaluated effectively in gouty arthritis ; (Lu et al., 2021;Wang et al., 2020;Zhou et al., 2023) offering insight on more effective alternatives to PPTN (Ko et al., 2007). Nevertheless, regardless of validated functions of the UDP-G/P2Y 14 R axis in animal models of diseases, approaches used to investigate P2Y 14 Rs are still relatively restricted; it is anticipated that more advanced approaches, such as optogenetics, chemogenetics, and improved molecular tools like metabolomics and histone modification, could help to gain a more comprehensive understanding of the molecular and metabolic pathways involved in UDP-G/P2Y 14 R-mediated inflammation, eventually leading to the discovery of a novel anti-inflammatory targets.

Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.

Funding
This work was supported by grants from the Innovation Team and Talents Cultivation Program of the National Administration of Traditional Chinese Medicine (ZYYCXTD-D-202003), and the Sichuan Science and Technology Program (2022YFH0006).

Declaration of competing interest
No.

Data availability
No data was used for the research described in the article. 10 μL/g of body weight the recruitment of neutrophils, eosinophils, and lymphocytes into the airway↓ MRS4815 displayed an even stronger potency than MRS4738 in reducing the recruitment of neutrophils, eosinophils, and lymphocytes into the airway Wen et al., 2022 For all abbreviations see the List of Abbreviations.