Inflammatory Bowel Diseases: It's Time for the Adenosine System

Antonioli, Luca; Fornai, Matteo; Pellegrini, Carolina; Bertani, Lorenzo; Németh, Zoltán; Blandizzi, Corrado

doi:10.3389/fimmu.2020.01310

Cited by 9 publications

(6 citation statements)

References 85 publications

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“…Our data also seem to support the investigation of future therapeutic approaches that aim to alter purinergic signaling cascades in IBD patients in order to dampen the overall inflammation (66). Treatment suggestions based on murine models include apyrase substitution (47), increase of the extracellular adenosine concentration via mucosa-specific inhibition of adenosine uptake (67), or HIF-1α stabilization (43,68,69).…”

Section: Discussionmentioning

confidence: 56%

Decreased Frequency of Intestinal CD39+ γδ+ T Cells With Tissue-Resident Memory Phenotype in Inflammatory Bowel Disease

et al. 2020

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The ectoenzymes CD39 and CD73 play a major role in controlling tissue inflammation by regulating the balance between adenosine triphosphate (ATP) and adenosine. Still, little is known about the role of these two enzymes and ATP and its metabolites in the pathophysiology of inflammatory bowel disease (IBD). We isolated mononuclear cells from peripheral blood and lamina propria of the large intestine of patients diagnosed with IBD and of healthy volunteers. We then comprehensively analyzed the CD39 and CD73 expression patterns together with markers of activation (HLA-DR, CD38), differentiation (CCR7, CD45RA) and tissue-residency (CD69, CD103, CD49a) on CD4 + , CD8 + , γδ + T cells and mucosa-associated invariant T cells using flow cytometry. CD39 expression levels of γδ + and CD8 + T cells in lamina propria lymphocytes (LPL) were much higher compared to peripheral blood mononuclear cells. Moreover, the frequency of CD39 + CD4 + and CD8 + , but not γδ + LPL positively correlated with T-cell activation. The frequency of CD39 + cells among tissue-resident memory LPL (Trm) was higher compared to non-Trm for all subsets, confirming that CD39 is a marker for the tissueresident memory phenotype. γδ + Trm also showed a distinct cytokine profile upon stimulation-the frequency of IFN-γ + and IL-17A + cells was significantly lower in γδ + Trm compared to non-Trm. Interestingly, we observed a decreased frequency of CD39 + γδ + T cells in IBD patients compared to healthy controls (p = 0.0049). Prospective studies need to elucidate the exact role of this novel CD39 + γδ + T-cell population with tissue-resident memory phenotype and its possible contribution to the pathogenesis of IBD and other inflammatory disorders.

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Section: Discussionmentioning

confidence: 56%

Decreased Frequency of Intestinal CD39+ γδ+ T Cells With Tissue-Resident Memory Phenotype in Inflammatory Bowel Disease

et al. 2020

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“…Conversely, adenosine has been shown to also have antiinflammatory effects through its action on the proteasomal degradation of IκB, and thus inhibiting NF-κB signaling ( 25 ), in addition to attenuating mucosal inflammation during acute colitis ( 48 ). These divergent effects of adenosine signaling during inflammation may be context dependent ( 49 ). Here, we find that extracellular 2′3′ cGAMP, through its hydrolysis to adenosine, down-regulates IFNβ expression induced by Poly I:C, surprisingly in an opposite manner to cytosolic CDNs.…”

Section: Discussionmentioning

confidence: 99%

Extracellular cyclic dinucleotides induce polarized responses in barrier epithelial cells by adenosine signaling

Chang

Whiteley

Gwilt

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Cyclic dinucleotides (CDNs) are secondary messengers used by prokaryotic and eukaryotic cells. In mammalian cells, cytosolic CDNs bind STING (stimulator of IFN gene), resulting in the production of type I IFN. Extracellular CDNs can enter the cytosol through several pathways but how CDNs work from outside eukaryotic cells remains poorly understood. Here, we elucidate a mechanism of action on intestinal epithelial cells for extracellular CDNs. We found that CDNs containing adenosine induced a robust CFTR-mediated chloride secretory response together with cAMP-mediated inhibition of Poly I:C-stimulated IFNβ expression. Signal transduction was strictly polarized to the serosal side of the epithelium, dependent on the extracellular and sequential hydrolysis of CDNs to adenosine by the ectonucleosidases ENPP1 and CD73, and occurred via activation of A2B adenosine receptors. These studies highlight a pathway by which microbial and host produced extracellular CDNs can regulate the innate immune response of barrier epithelial cells lining mucosal surfaces.

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“…MTX and especially its metabolites polyglutamates are capable of inhibiting 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase; subsequently, there is an adenosine accumulation [ 107 , 110 ]. Adenosine exerts antioxidant and anti-inflammatory effects by both regulating the CD39/CD73 axis, involved in its synthesis, and binding to adenosine receptors [ 108 , 111 , 112 ].…”

Section: Association Between the Gm And Drugs Used For The Treatmementioning

confidence: 99%

Microbiota and Drug Response in Inflammatory Bowel Disease

et al. 2021

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A mutualistic relationship between the composition, function and activity of the gut microbiota (GM) and the host exists, and the alteration of GM, sometimes referred as dysbiosis, is involved in various immune-mediated diseases, including inflammatory bowel disease (IBD). Accumulating evidence suggests that the GM is able to influence the efficacy of the pharmacological therapy of IBD and to predict whether individuals will respond to treatment. Additionally, the drugs used to treat IBD can modualate the microbial composition. The review aims to investigate the impact of the GM on the pharmacological therapy of IBD and vice versa. The GM resulted in an increase or decrease in therapeutic responses to treatment, but also to biotransform drugs to toxic metabolites. In particular, the baseline GM composition can help to predict if patients will respond to the IBD treatment with biologic drugs. On the other hand, drugs can affect the GM by incrementing or reducing its diversity and richness. Therefore, the relationship between the GM and drugs used in the treatment of IBD can be either beneficial or disadvantageous.

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Inflammatory Bowel Diseases: It's Time for the Adenosine System

Cited by 9 publications

References 85 publications

Decreased Frequency of Intestinal CD39+ γδ+ T Cells With Tissue-Resident Memory Phenotype in Inflammatory Bowel Disease

Decreased Frequency of Intestinal CD39+ γδ+ T Cells With Tissue-Resident Memory Phenotype in Inflammatory Bowel Disease

Extracellular cyclic dinucleotides induce polarized responses in barrier epithelial cells by adenosine signaling

Microbiota and Drug Response in Inflammatory Bowel Disease

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