Abstract
Background
Adenosine, acting as a regulator by mediating the activation of G protein-coupled adenosine receptor families (A1, A2A, A2B, and A3), plays an important role under physiological and pathological conditions. As the receptor with the highest affinity for adenosine, the role of adenosine A1 receptor (A1R)-mediated adenosine signaling pathway in the central nervous system has been well addressed. However, functions of A1R on immune cells are less summarized. Considering that some immune cells express multiple types of adenosine receptors with distinct effects and varied density, exogenous adenosine of different concentrations may induce divergent immune cell functions.
Materials and methods
The literatures about the expression of A1R and its regulation on immune cells and how it regulates the function of immune cells were searched on PubMed and Google Scholar.
Conclusion
In this review, we discussed the effects of A1R on immune cells, including monocytes, macrophages, neutrophils, dendritic cells, and microglia, and focused on the role of A1R in regulating immune cells in diseases, which may facilitate our understanding of the mechanisms by which adenosine affects immune cells through A1R.
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Introduction
Adenosine is an endogenous small molecule that arises from the release of equilibrium transporters or from cell damage, but it is mainly produced by the hydrolysis of adenosine triphosphate through membrane-bound nucleotide enzymes: ectonucleoside triphosphate diphosphohydrolase-1 (CD39) and ecto-5′-nucleotidase (CD73) [1, 2]. Adenosine regulates cells and organs primarily through the downstream signals by its interaction with four G protein-coupled receptors (GPCRs), named A1, A2A, A2B, and A3 adenosine receptors, which are expressed in different cells and tissues in the body [3]. Under physiological conditions, the expression level of adenosine is low, usually in the range of 20–300 nM [4]. However, under ischemia and hypoxia as in the cases of necrosis and tumors, the concentration of adenosine in the tissue will reach micromolar level [5]. Under such condition, high concentrations of adenosine can regulate different immune cells by activating adenosine receptors, thereby affecting the function of immune cells under pathological conditions.
Adenosine has an impact on a variety of physiological aspects, such as neuronal activity, vascular function, and blood cell regulation [6]. The combination of adenosine with four different adenosine receptors and the different distribution of adenosine receptors on cells commonly indicate different regulatory functions [5]. A1 and A3 receptors inhibit the activity of adenylyl cyclase (AC) by coupling to the Gi protein, while A1 receptor (A1R) is mainly expressed in the central nervous system and A3 receptor is widely expressed by a variety of primary cells and tissues. However, the A2 receptors, including A2A and A2B receptors, are coupled to Gs proteins. The A2A receptor, a high-affinity receptor, is expressed both centrally and peripherally, while A2B receptor, a low-affinity receptor, is mainly expressed in the peripheral area. Both of them activate AC mainly through the Gs protein, thereby promoting the production of cAMP [5, 7].
Different adenosine receptors have different affinities for adenosine. The A1R shows the highest affinity for adenosine, which can reach 1–10 nM. The A1R subtypes are expressed in large quantities in the central nervous system and are also abundant in other organs, such as the heart, kidneys, lungs, and livers, to regulate the functions of the organs themselves [8]. The A1R in the kidneys is able to regulate proximal tubular sodium transport and fluid balance mediated by the tension of the afferent substance [9]. In allergic reactions, adenosine is able to cause bronchial contractions in humans by activating A1R [10]. Studies related to the central nervous system have shown that the A1R signaling has an effect on both sleep and the development of central nervous system [11]. The distribution of A1R is also closely related to the main sites of cerebral infarction [12]. It is worth noting that the A1R is also expressed on various immune cells, such as monocytes, macrophages, neutrophils, and dendritic cells, but not on T cells and NK cells [13]. The A1R-mediated signaling plays an important regulatory role in the growth and development of immune cells and their functional differentiation, but there is no relevant literature summarizing this aspect of A1R in immune cells. Based on this, this review mainly summarizes the effect of A1R on different immune cells in the immune system and its latest research progress, which may provide reference for the future clinical application of A1R-related treatments.
Adenosine A1 receptor
Structure
The A1R is a glycoprotein with a molecular mass of ~ 36 kDa and contains a total of 326 amino acids [11, 14]. Similar to other adenosine receptors, the A1R belongs to the G protein-coupled receptor family and contains a seven-fold transmembrane structure [15]. The seven transmembrane α-helix structures are connected by three extracellular domains and three intracellular domains, with the C-terminal remaining in the intracellular region [16]. The N-terminus and extracellular domains are responsible for ligand binding, while the C-terminal and intracellular domains bind to G proteins and then transduce the downstream signals [11]. The length of intracellular C-terminus in A1R is shorter than other adenosine receptors, with only 36 amino acids [3, 17]. The sequence of the A1R is more conserved among species [18]. A comparative study of rat, dogs, bovines, and humans shows that about 90% of the coding regions of the A1R are similar [14].
Signaling pathways
The A1R and the second messenger are coupled in a manner similar to A3 receptor, which are different from the A2A and A2B receptors. After A1R receives adenosine signal, the Pertussis toxin-sensitive Gi and/or Go proteins are activated, which results in the breakdown of G protein α and G protein β/γ isomers, and the GDP is converted to GTP after binding G protein α. G protein α-i inhibits the activity of AC, thus subsequent synthesis of cAMP, thereby restraining the weakening of the phosphorylation of cAMP-dependent protein kinase A (PKA) [19]. The G protein β/γ receptors bind to and activate phospholipase C-β (PLC-β), catalyzing PIP2 to form PI3. The PI3 then mobilizes internally stored calcium ions to activate the protein kinase C (PKC) protein, which plays an important role in the activation of the NF-κB pathway [20, 21]. At the same time, A1R also causes activation of the ERK1/2 pathway by releasing the β/γ subunits of G protein (Fig. 1) [22, 23].
Overview of A1R signaling pathways. Stimulation of A1R decreases adenylates cyclase (AC) activity and cAMP production, thus inhibiting protein kinase A (PKA), while it activates phospholipase C (PLC)-β to catalyze PIP2 to form PI3. The activation of A1R also inhibits Ca2+ influx and promotes K+ outflow [96]. Mitogen-activated protein kinases ERK1/2 phosphorylation is induced by A1R activation
Agonists and antagonists
Most of the A1R agonists are modification products of adenosine, which are mainly modified at three positions in adenosine [24]: N6-position, C2 position, and 5′-position. CHA (N6-cyclohexyladenosine) and CPA (N6-cyclopentyladenosine) are just two examples of modification at the N6-position [24, 25]. The use of hydrophobic cycloalkyl monosubstitution at the N6-position of adenosine provides high selectivity for A1R (Fig. 1) [25]. The introduction of chlorine atoms at the C2 position, such as CCPA, increases the selectivity of A1R [1, 26]. Various agonists, such as NECA (5′-N-ethylcarboxamidoadenosine), MRS5595, and MRS5607, are generated by the addition of formamide derivatives at the 5′-position in the ribose unit of adenosine, which also confers special selectivity to A1R [27].
Antagonists of A1R are mainly divided into xanthine derivatives and non-xanthine. Most of the A1R selective antagonists are mainly obtained by substitution of aromatic and cycloalkyl groups at C8 position of the xanthine. Interestingly, substitution at the N1, N3, and N7 positions can enhance the selectivity of A1R [24]. Common xanthine derivative antagonists against A1R mainly include DPCPX (8-cyclopentyl-1,3-dipropylxanthine) [28, 29] and rolofylline [30] (Fig. 1). In terms of non-xanthine antagonists, many heterozygous compounds have been found to be able to antagonize adenosine receptors, such as FK-453, a derivative of pyrazolo [1,5-a] pyridine, which has a high selectivity and antagonistic effect on A1R [31, 32]. In addition, some derivatives of adenine have been continuously explored to act as antagonists of A1R. The addition of isopropyl methylamine in the 8-position of adenine (WRC-0571) greatly increases its antagonism and water solubility [33].
Effect of A1R on monocytes and macrophages
Differentiation
The A1R plays an important role in the maturation and differentiation of monocytes. The expression level of A1R on monocytes and macrophages is lower than that of A2A and A2B receptors [34, 35]. During bone growth and development, monocytes fuse into multinucleated giant cells and eventually differentiate into osteoclasts [36]. However, the activation of A2A and A2B receptors can inhibit the formation of osteoclasts [37]. In contrast, studies have shown that A1R expressed on monocytes can be activated by changing the TRAF6/TAK1 signaling pathway, which promotes the monocytes by macrophage colony-stimulating factor (M-SCF) and receptor activator of nuclear factor-κB ligand (RANKL) to form multinucleated osteoclasts [38, 39]. After administering rolofylline, an A1R antagonist, the number of monocytes differentiating into osteoclasts is significantly reduced. In addition, the intensity of this reduction is positively correlated with the increase of rolofylline concentration, suggesting that blocking A1R can inhibit the differentiation of monocytes into osteoclasts [37, 40]. In accordance with the in vitro results, studies in vivo also confirm the reduction of osteoclasts in bone resorption and bone loss after ovarian resection by knocking out adenosine A1 receptor gene (ADORA1) or using DPCPX as an antagonist to block the signal of A1R [41]. Taken together, the stimulation of A1R signaling is of great importance for the differentiation of monocytes into osteoclasts. Meanwhile, the A1 receptor-selective agonist N5-cyclopentyl adenosine (CPA) promotes, while the A1 receptor antagonist 8-cyclopentyl-dipropylxanthine inhibits the formation of giant cells [42]. Landells et al. found that CPA inhibited the proliferation of monocytes in patients with asthma [35]. In summary, most of the results suggest that adenosine is able to promote the proliferation and differentiation of monocytes by activating A1R.
Inflammatory response
Apart from modulating the differentiation of monocyte, the activation of A1R can also regulate the cytokine production of monocytes and macrophages. Studies performed by Eudy and Sliva have demonstrated that the A1R is required for the secretion of adenosine-stimulated interleukin (IL)-10 and IL-1β [43]. Only knocking out ADORA1 in THP-1 macrophages can eliminate the secretion of IL-10 by exogenous adenosine [35]. Macrophages from ADORA1 knockout (KO) mice show increased expression of the pro-inflammatory genes, IL-1, and matrix metalloproteinase (MMP)-12 after immune activation [44]. In CD73-deficient tumors, the stimulation by A1R leads to significant downregulation of the pro-MI (classically activated macrophage) cytokine granulocyte macrophage colony-stimulating factor (GM-CSF), and of the pro-MII (alternatively activated macrophage) cytokines IL-10 and M-SCF [45]. Notably, both IL-10 and M-CSF are reported to affect the polarization and infiltration of macrophages [46]. Therefore, these results indicate that the exogenous adenosine can regulate the polarization and infiltration of macrophages through A1R.
It has been shown that both A1 and A2 receptor agonists suppress the production of TNF-α by RAW 264.7 macrophage cell line or human monocytes [47]. However, it is still controversial about whether the production of nitric oxide (NO) by macrophages is affected under A1R activation. Some studies have shown that the selective A1R agonist CCPA can inhibit LPS-stimulated NO production in RAW264.7 macrophage cell line by activating A1R [48], while others have reported that the activation of adenosine receptors with LPS stimulation may increase the expression of nitric oxide synthase (NOS) and NO [49, 50]. These controversial results illustrate that the distinct effector functions of monocytes induced by signaling through A1R alone and through A1R plus other adenosine receptors. Considering the fact that monocytes express both A1 and A2 receptors and these receptors can induce opposite cAMP-related signaling pathways, it is interesting to know whether different concentrations of adenosine have different effects on monocyte function by regulating the cAMP-related signaling pathways.
Notably, the expression of A1R affects the function and inflammatory responses of macrophages. In a rat stroke model, A1R is expressed on infiltrating macrophages. The reactivation and proliferation of both microglia and macrophages are reduced when A1R is activated, which protects rats from ischemic injury after stroke [51]. In patients with ankylosing spondylitis, the mRNA level of A1R on macrophage is 2.5-fold lower than normal macrophages, suggesting the involvement of A1R in regulating the inflammatory response of macrophages [52]. In patients with multiple sclerosis, the expression level of A1R, but not A2 receptors, decreases in both mononuclear cells and macrophages in brain and blood, implying a reduced ability of adenosine to regulate macrophage-mediated inflammation through A1R, thereby promoting the progression of multiple sclerosis [53]. In allergic reactions, the expression of A1R on sputum macrophages has decreased, which also prevents adenosine from regulating inflammation in the airway/sputum, which illustrates the possibility that allergens cause inflammation and weakening of symptoms due to insufficient adenosine to regulate the inflammatory response [54]. Taken together, the decreased expression of A1R increases the involvement of macrophage in inflammation, illustrating the importance of A1R signaling in reducing macrophage-mediated inflammatory responses.
Effect of A1R on neutrophils
Chemotaxis
Neutrophils are affected by the activation of A1R in many aspects, such as chemotaxis, adhesion, and anti-inflammation. Previous results suggest that the migration of neutrophils to injured tissues is regulated through the involvement of A2 receptors [55]. Later, by using different agonists, Cronstein et al. have demonstrated that the downstream G protein-linked receptor-mediated mechanism after A1R activation and the involvement of intact microtubules were the main reasons for increased neutrophil migration [56]. Moreover, the migration of neutrophil is also related to adenosine concentration. When the concentration of adenosine is low, it mainly binds to A1R to promote the migration of neutrophils to inflammatory tissues rather than healthy tissues. When the concentration of adenosine is high, it mainly binds to A2 receptors to inhibit the production of toxic oxygen metabolites, thereby inhibiting the effect of activated neutrophils on damaged tissues to avoid further damage [56]. This feature may contribute to the distinct behavior of adenosine-induced neutrophil chemotaxis in different disease models. For example, during bacterial infection, the migration of neutrophils is inhibited by LPS [57]. However, the activation of A1R on neutrophils by reception of adenosine signaling can restore their migration ability. This restoration is caused by the downstream activation of p38MAPK pathway [57]. In this scenario, A1R signaling can benefit neutrophil migration. However, in other cases, A1R signaling inhibits neutrophil migration/infiltration. In a study of spinal cord adenosine receptors, intrathecal catheter injection of A1R agonists significantly reduced neutrophil infiltration at sites of dermal inflammation [58]. In addition, neutrophil infiltration is a major feature of ischemia–reperfusion (IR) injury, but various studies have shown that activation of A1R can alleviate this condition [59,60,61,62,63,64]. It is demonstrated that the ischemic intestinal injury is reduced by using adenosine to activate A1R, because the activation of A1R decreases the infiltration of neutrophils and increases the content of glutathione [59]. In a pulmonary IR model, treatment with A1R agonist CCPA in mice reduced the expression of inflammatory cytokines and neutrophils infiltration, and neutrophils were absent in A1R KO mice [60]. Myeloperoxidase (MPO) is considered as an indicator of neutrophil activation and infiltration into alveolar airspaces. The expression level of MPO in bronchoalveolar lavage fluid rises significantly after IR treatment, but decreases significantly in wild-type (WT) mice after activating the A1R [60, 61]. In kidney and liver IR models, the activation of A1R can reduce apoptosis, necrosis, neutrophil infiltration, and inflammatory cytokine production [62,63,64]. In contrast, studies by Forman et al. showed that the blockade of A1R with A1R antagonists attenuated myocardial IR injury, primarily by reducing the chemotaxis response of neutrophils to formyl-Met-Leu-Phe [65]. Taken together, these results suggest that the neutrophil chemotaxis in different disease models relies on the signaling of A1R alone or A1R along with other adenosine receptors.
Adhesion
Adenosine can promote the adhesion of neutrophils through A1R, and this regulation may assist in neutrophil chemotaxis [66]. It is different from the occupation of A2 receptor, which inhibits the adhesion of neutrophils [66]. A study showed that A1R agonist COPA increased PMA-stimulated neutrophil-endothelial cell adhesion by 30% [67]. After entering the injured tissue, neutrophils can migrate to the vascular endothelium through the adhesion of endothelial cells and can be activated upon immune stimulation [68]. To be specific, this activation is mainly due to the activation of cell surface integrins during cell motility and the further binding of very late antigen 4 (VLA-4) to molecules on vascular endothelial cells [68]. However, Cronstein et al. proved that A1R was able to increase human neutrophil adhesion to gelatin plates rather than to fibrinogen (a ligand for the beta 2 integrin CD11b/CD18), indicating that the enhancement of neutrophil-to-endothelial cell adhesion by A1R is not through the traditional neutrophil integrins [66].
Inflammatory response
Activation of the A1R also affects the inflammatory function of neutrophils. Bhalla et al. demonstrated that aged mice failed to efficiently eliminate Streptococcus pneumococci compared with young mice, which could be rescued by providing adenosine to aged mice. They further showed that the inhibition of A1R impaired the ability of mouse polymorphonuclear cells to kill Streptococcus pneumococci [69]. The activation of A1R using agonists restored the ability of polymorphonuclear cells in aged mice to kill engulfed Streptococcus pneumoniae. In addition, A1R agonists can enhance Fcγ receptor-mediated phagocytosis and superoxide production of neutrophils [70, 71]. Meanwhile, plasma adenosine deaminase can enhance the release of toxic oxygen free radicals in neutrophils and promote the development of inflammation by stimulating the A1R [72].
In summary, activation of A1R enhances the inflammatory effect of neutrophils and promotes their migration to the inflammatory sites. However, in many IR models, activation of A1R can reduce neutrophil infiltration and inflammation, which indicates the role of A1R in adenosine therapy for relieving inflammation under organ transplantation.
Effect of A1R on dendritic cells
Chemotaxis
Dendritic cells (DC) are highly differentiated antigen-presenting cells. DC cells are divided into three categories, namely, conventional dendritic cells (cDCs), plasmacytoid dendritic cells (pDCs), and monocyte-derived dendritic cells (moDCs) [73]. To be specific, the cDCs are determined according to their ontogenic development and phenotype. The pDCs can differentiate into DC-like antigen-presenting cells and can stimulate T cell responses, while producing a large amount of type I interferon [74, 75].The moDCs can share phenotypic markers with cDCs as antigen-presenting cells in tissues. It seems that different types of DCs manifest different expression tendency of adenosine receptors. For example, the human immature moDCs express A1 and A3 receptors, while immature pDCs express only A1R [76]. Under physiological conditions, extracellular adenosine (nM to low μM) significantly increases intracellular calcium concentration by activating A1R, promoting the migration of immature human pDCs to locations with high concentration of adenosine. Activation of A1R can induce a stronger calcium influx and actin recombination than the A3 receptor, leading to the migration of immature moDCs [77]. After treatment with the A1R agonist CHA, the drive-up effect of pDCs is enhanced, while this phenomenon is not present with the treatment of other adenosine receptor agonists. What is more, the chemotactic effect disappears after the inhibition of A1R. During the maturation of pDCs stimulated with CD40L, the mRNA level of A1R is reduced and chemotactic effect by adenosine is not found [76]. This suggests that A1R is able to induce adenosine-dependent chemotaxis in immature pDCs, which may cause immature pDCs to migrate to the sites with high concentrations of adenosine, where they can induce an immune response and differentiate into mature pDCs.
Differentiation
moDCs are mainly differentiated from CD14+ monocytes in peripheral blood in vitro. Under the stimulation of GM-CSF and IL-4, the monocytes will differentiate into immature CD14+CD1a+ MoDCs, and then moDCs will further maturate with the stimulation of LPS [77]. The mRNA level of A1R on immature moDCs is higher than that on mature moDCs. However, when stimulated by LPS, the expression level of A2A and A2B receptor increases on DCs, while the expression level of A1R decreases or is absent [34, 77]. Whether A1R affects the differentiation of DCs is controversial. Novitskiy et al. showed that the activation of A1R did not affect the differentiation of DCs, while Panther et al. showed that the increased expression of A1R on moDCs and differentiation of immature moDCs were significantly correlated. Interestingly, Yasui et al. found that the activation of A1 and A2A receptors could alleviate theophylline, a substance that inhibits DCs differentiation, and then inhibit the monocyte differentiation into DCs, suggesting that the A1R may cooperate with A2A receptor in the differentiation and survival of DCs [78].
Inflammatory response
DCs show high sensitivity to adenosine in the inflammatory response. It has been reported that adenosine mainly blocks the inherent response of DCs through the A1R signaling, then reduces the expression of inflammatory factors, including IL-2 and TNF-α, and finally inhibits the effect of DC-mediated inflammation [79]. In addition, adenosine exerts a strong inhibitory effect on vesicular MHC-I cross-presentation in resting DCs through A1R [80], which may affect the immunomodulation in the surrounding T cell pools.
A1R can sense low level of adenosine through its higher affinity for adenosine under physiological conditions, thereby regulating the migration and differentiation of immature monocytes and the expression of DC-secreted cytokines. In summary, A1R might be a potential activator for modulating immature DCs.
Effect of A1R on microglia
Microglia are main immune surveillance cells in brain, responding early to injury. After brain injury, microglia deform and metastasize to the damaged site, playing an important role in the neuroinflammatory responses [81, 82]. The mechanism of microglia migration is that a large amount of ATP and ADP are generated at the injury site, and the Gi/o-coupled P2Y receptors of microglia are activated to generate chemotaxis [83]. Compared with ATP, adenosine mainly affects the activation of microglia through A1R.
A1R is widely expressed on microglia, and the proportion of A1R expressed on mouse microglia is more than 97% [84]. Primary-cultured microglia of rat highly express A1R and A3 receptors and lowly express A2A receptor [85]. After nerve injury in the brain, the microglia migrate to the damaged site, secrete a variety of cytokines, phagocytose cell debris, and promote tissue repair and nerve regeneration [86]. It has been shown that activated A1R by agonists can inhibit the microglia inflammatory response caused by TNF-α, IL-1β, and IFN-γ [87]. In multiple sclerosis model, increased expression of pro-inflammatory genes, decreased expression of anti-inflammatory genes, and enhanced activation of microglia/macrophages are observed in the spinal cord of ADORA1 knockout mice compared to WT mice [44]. Moreover, mice with the ADORA1 gene knocked out are more pronounced in demyelination deterioration and axonal damage [44]. Taken together, these results may shed light on future treatments for neuroinflammation-related diseases, such as Alzheimer's disease, Parkinson’s disease, and multiple sclerosis [87].
In the central nervous system, the activation of A1R is primarily responsible for negative excitatory transmission, while the activation of A2A receptor promotes synaptic plasticity [88]. The activation of A1R has an inhibitory effect on microglia in brain trauma mice [89]. To be specific, CX3CL1 mediates neuroprotective effects in different brain injury models through its inhibitory activity against microglia, but this regulation requires the presence and activation of A1R [90, 91]. Moreover, these effects are eliminated in mice with A1R deletion or after treatment with A1R antagonists [90]. Selective stimulation of A1R inhibits morphological activation of microglia, and microglia treated with A1R agonists have reduced ability to promote nociceptive neurons [84]. Chronic treatment with another A1R agonist, 5′-chloro-5′-deoxy-( ±)-ENBA, is able to reduce neuropathic pain in mice by reducing activated microglia [92]. However, simultaneous stimulation of adenosine A1 and A2 receptors can promote the proliferation of microglia [93]. In summary, A1R mainly reduces inflammatory response by inhibiting the activity of microglia, regulates the immune balance at the brain injury site, and prevents excessive immune response.
Conclusion
A1R, the receptor with the highest affinity with adenosine, has been shown to play an important role in inflammation and disease. The activation of A1R can promote the differentiation and migration of some immune cells, as well as regulate the inflammatory response of immune cells after using A1R activators (Fig. 2). This phenomenon suggests that A1R may play a role in regulating the balance of immune cell activity in diseases, thereby preventing excessive immune responses at the site of inflammation. Apart from the above mentioned cell types, in vitro study also shows that activated B cells are able to express A1R [94], and the A1R-mediated autocrine signaling can regulate the function of B cells [95]. In conclusion, the activation of A1R plays an important role in the growth and function of different types of immune cells, which may provide guidance for clinical application of agonists and antagonists of A1R in the future.
Schematic diagram illustrating the role of A1R on different types of immune cells. Activation of A1R signaling pathway by adenosine can affect many immune cells, including monocytes, macrophage, dendritic cells, neutrophils, and microglia, resulting in various biological outcomes
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This work was supported by the National Natural Science Foundation of China (31870899 and 32070899 to X.Z., 82103304 to Q.P.) and the Independent Task of State Key Laboratory for Diagnosis and Treatment of Infectious Diseases (2022zz07 to Q.P.).
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LZ drafted the main body of this manuscript and drew the figures. QP modified the manuscript. XZ takes primary responsibility for this paper as the corresponding author. All authors contributed to the article and approved the submitted version.
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Zhong, L., Peng, Q. & Zeng, X. The role of adenosine A1 receptor on immune cells. Inflamm. Res. 71, 1203–1212 (2022). https://doi.org/10.1007/s00011-022-01607-w
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DOI: https://doi.org/10.1007/s00011-022-01607-w