Activation of A2A Adenosine Receptor Attenuates Intestinal Inflammation in Animal Models of Inflammatory Bowel Disease

Odashima, Masaru; Bamias, Giorgos; Rivera–Nieves, Jesús; Linden, Joel; Nast, Cynthia C.; Moskaluk, Christopher A.; Marini, Marco; Sugawara, Kazuhiko; Kozaiwa, Kosuke; Otaka, Michiro; Watanabe, Sumio; Cominelli, Fabio

doi:10.1053/j.gastro.2005.05.032

Cited by 189 publications

(176 citation statements)

References 26 publications

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“…Indeed, ATP levels were reduced in the intestine of patients with IBD,47, 48, 49 and expression of the A2A receptor was upregulated in inflamed colons. Studies have shown that selective agonists for activation of the A2A receptor reduced tissue damage in various animal models of IBD 44, 50. Our results provide new insights into how alterations in purine metabolism in response to tissue damage modulate the pathophysiology of IBD, that is, through interaction with the ILC3‐IL‐22 pathway.…”

Section: Discussionmentioning

confidence: 63%

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: Discussionmentioning

confidence: 63%

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

et al. 2018

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“…27 At the height of inflammation, the destruction of host tissue combined with damaged microcirculation and hypoxia leads to elevation of extracellular adenosine. 28 Animal models of asthma, 29 arthritis, 30 sepsis, 31 inflammatory bowel disease 32 and wound healing 33 have helped to elucidate the regulatory roles of adenosine in dictating the development and progression of disease. Adenosine potently inhibits a wide range of T-cell responses, including cell proliferation, 34 synthesis of IL-2 and proinflammatory cytokines, such as IFN-c and TNF-a, 35 and some of the earliest steps of T-cell activation, which were reported to be mediated mainly by the adenosine A 2A receptor.…”

Section: Pf Inhibits the Functions Of T Cells And Differentiation Of mentioning

confidence: 99%

Pleural fluid from tuberculous pleurisy inhibits the functions of T cells and the differentiation of Th1 cells via immunosuppressive factors

Liu

et al. 2011

Cell Mol Immunol

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Immunosuppressive mediators in tuberculosis pleurisy (pleural fluid (PF)) are associated with the course of disease, but they remain poorly defined. To study the local immune status of patients with tuberculosis pleurisy, we examined the effect of PF on the functions of T cells and the differentiation of Th1 cells. PF could inhibit the ability of T cells to produce cytokines. However, tumor-necrosis factor (TNF)-a derived from non-T cells was not impaired. Further analysis indicated that cell activation and cell cycle progression were also suppressed. Moreover, PF could inhibit Th1 cell differentiation. Importantly, we found that inhibitors of indoleamine 2,3-dioxygenase (IDO) and adenosine and neutralizing antibodies against IL-10 and transforming growth factor (TGF)-b could reverse cytokine production, suggesting that IDO, adenosine, IL-10 and Transforming growth factor-b1 in PF might take part in impairing T-cell functions. Taken together, our data demonstrate for the first time that several immunopathological factors participate in the downregulation of T-cell functions in local PF.

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“…Other studies have shown that stimulation of A 2A receptors can reduce inflammation in the intestinal mucosa in rabbits and mice [111] and reduce tissue injury and inflammation in mice with toxin A-induced enteritis [112]. A recent study utilized a high-density oligonucleotide microarray analysis to study TNBS-induced colitis [113].…”

Section: Intestinal Pathologies and Purinergic Signalingmentioning

confidence: 99%

Purinergic receptors and synaptic transmission in enteric neurons

Ren

Bertrand

2007

Purinergic Signalling

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Purines such as ATP and adenosine participate in synaptic transmission in the enteric nervous system as neurotransmitters or neuromodulators. Purinergic receptors are localized on the cell bodies or nerve terminals of different functional classes of enteric neurons and, with other receptors, form unique receptor complements. Activation of purinergic receptors can regulate neuronal activity by depolarization, by regulating intracellular calcium, or by modulating second messenger pathways. Purinergic signaling between enteric neurons plays an important role in regulating specific enteric reflexes and overall gastrointestinal function. In the present article, we review evidence for purine receptors in the enteric nervous system, including P1 (adenosine) receptors and P2 (ATP) receptors. We will explore the role they play in mediating fast and slow synaptic transmission and in presynaptic inhibition of transmission. Finally, we will examine the molecular properties of the native receptors, their signaling mechanisms, and their role in gastrointestinal pathology. Keywords

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Activation of A2A Adenosine Receptor Attenuates Intestinal Inflammation in Animal Models of Inflammatory Bowel Disease

Cited by 189 publications

References 26 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

Pleural fluid from tuberculous pleurisy inhibits the functions of T cells and the differentiation of Th1 cells via immunosuppressive factors

Purinergic receptors and synaptic transmission in enteric neurons

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