Purinergic regulation of the immune system

Cekic, Caglar; Linden, Joel

doi:10.1038/nri.2016.4

Cited by 602 publications

(580 citation statements)

References 207 publications

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“…Consistently, gene expression of A2A rather than other adenosine receptors was upregulated in inflamed colons compared to control colons in humans. As the A2A receptor dominantly activates the cAMP signaling pathway,7 these results are consistent with our previous findings that ILC3 activation and IL‐22 production were positively regulated by another cAMP elevating reagent prostaglandin E 2. 22 Therefore, both downregulation of ATP signaling and upregulation of adenosine signaling may contribute to NTPDase‐dependent enhancing IL‐22 production from ILC3s, leading to protection against intestinal inflammation.…”

Section: Discussionsupporting

confidence: 92%

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Purine metabolism controls innate lymphoid cell function and protects against intestinal injury

et al. 2018

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Inflammatory bowel disease (IBD) is a condition of chronic inflammatory intestinal disorder with increasing prevalence but limited effective therapies. The purine metabolic pathway is involved in various inflammatory processes including IBD. However, the mechanisms through which purine metabolism modulates IBD remain to be established. Here, we found that mucosal expression of genes involved in the purine metabolic pathway is altered in patients with active ulcerative colitis (UC), which is associated with elevated gene expression signatures of the group 3 innate lymphoid cell (ILC3)–interleukin (IL)‐22 pathway. In mice, blockade of ectonucleotidases (NTPDases), critical enzymes for purine metabolism by hydrolysis of extracellular adenosine 5′‐triphosphate (eATP) into adenosine, exacerbates dextran‐sulfate sodium‐induced intestinal injury. This exacerbation of colitis is associated with reduction of colonic IL‐22‐producing ILC3s, which afford essential protection against intestinal inflammation, and is rescued by exogenous IL‐22. Mechanistically, activation of ILC3s for IL‐22 production is reciprocally mediated by eATP and adenosine. These findings reveal that the NTPDase‐mediated balance between eATP and adenosine regulates ILC3 cell function to provide protection against intestinal injury and suggest potential therapeutic strategies for treating IBD by targeting the purine–ILC3 axis.

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Section: Discussionsupporting

confidence: 92%

“…Cell‐surface ectonucleotidases (NTPDases) such as NTPDase1 (i.e. CD39), together with the ecto‐5′‐nucleotidase CD73, hydrolyze eATP to adenosine, a purine nucleoside with anti‐inflammatory effects 3, 6, 7. NTPDase1 is present at high levels in intestinal tissues from patients with IBD 8.…”

Section: Introductionmentioning

confidence: 99%

Purine metabolism controls innate lymphoid cell function and protects against intestinal injury

et al. 2018

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“…Interestingly, the genes in the P2RY1 and P2RY12 pathways are predominantly G protein-coupled receptors and signaling components belonging to the family of P2Y receptors. These receptors are widely expressed in neuronal and neuroglial cells as well as peripheral leukocytes and are known to play important roles in eliciting proinflammatory responses (21). They have previously been shown to be involved in the initiation and modulation of visceral, cutaneous, and MSK neuropathic as well as inflammatory pain following trauma and infection (22).…”

Section: Resultsmentioning

confidence: 99%

Early molecular correlates of adverse events following yellow fever vaccination

Chan¹,

Chan²,

Chua³

et al. 2017

JCI Insight

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confidence: 99%

Adenosine in the Bone Marrow Myeloma Niche: Immune Checkpoint and Key Player in the Progression of Myeloma Disease

Horenstein¹,

Quarona²,

Morandi³

et al. 2017

J Cell Signal

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CommentaryThe tumor microenvironment is rich extracellular mono-and dinucleotides (ATP, NAD+), which are metabolized by cell surface ecto enzymes to produce increased local concentrations of adenosine (Ado), a nucleoside involved the control of inflammation and immune responses [1]. A recent study by our group demonstrated that adenosinergic pathways contribute to customize the immune homeostasis of multiple myeloma (MM) [2]. A plasma cell malignancy, MM prevalently develops and expands with bone marrow (BM) niches [3]. Malignant plasma cells at all stages of the disease overexpress CD38 [4], a molecule with widespread tissue distribution and complex functions not yet fully elucidated. CD38 is a 45-kDa type II (or III) trans membrane glycoprote expressed by several immune and nonimmune cell types, and it plays a dual role as a receptor and as an ectoenzyme [5]. As a nucleotide-metabolizing ectoenzyme, CD38 catalyzes at neutral pH the extracellular conversion of a dinucleotide of adenine (NAD + ) to cADPR and ADPR. At acidic pH, CD38 can also catalyze the exchange of the nicotinamide group of NADP + with nicotinic acid and produce NAADP + and ADPRP.All of the final products are basic regulators of calcium signaling [6]. The initial disassembly of NAD + is followed by adenosinergic activity, provided that CD38 is operating the presence of other ectoenzymes (ectonucleotide pyrophosphatase/phosphodiesterase CD203a and 5'-nucleotidase CD73). These findings point to the existence of an alternative axis for extracellular production of the immunosuppressive Ado. Such a pathway would be able to flank and, some instances, to bypass the canonical pathway based on the conversion of ATP by the ecto-nucleoside triphosphate diphosphohydrolase CD39 [7,8]. These coordinated networks may be hijacked by the tumour for its own purposes.These observations are relevant to myeloma homeostasis the BM. For energy production and the synthesis of nucleotides and other macromolecules, malignant plasma cells favour glycolysis over oxidative phosphorylation (the Warburg effect), thus sacrificing efficiency for speed. This metabolic shift is hallmarked by hypoxic conditions, and leads to a decrease ATP concentrations and a concurrent increase NAD+ levels to susta high-rate glycolysis. this context, extracellular Ado may originates and be released from tumor cells depleted of ATP, or it may derive from extracellular ATP and NAD+ leaked from damaged tumor tissues.As a consequence, Ado may assume the role of a local hormone, adjusting cellular metabolism either via low or high affinity specific receptors expressed by normal and tumor cells [5]. Evidence for this is our finding that CD56 bright CD16 + NK cells produce Ado through a CD38-mediated pathway [9]. The functional relevance is that these NK cells operate as activated immune effector/regulatory cells inhibiting autologous CD4+ T cell proliferation. This strategy of immune escape has already been observed: melanoma cells produce Ado through a CD38/CD203a/CD73 pathway and suppress CD4+ T ce...

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Purinergic regulation of the immune system

Cited by 602 publications

References 207 publications

Purine metabolism controls innate lymphoid cell function and protects against intestinal injury

Purine metabolism controls innate lymphoid cell function and protects against intestinal injury

Early molecular correlates of adverse events following yellow fever vaccination

Adenosine in the Bone Marrow Myeloma Niche: Immune Checkpoint and Key Player in the Progression of Myeloma Disease

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