Control of Interferon‐alphaA by CD73: Implications for Mucosal Inflammation

Louis, Nancy A.; Robinson, Andreas; Karhausen, Joern; Scully, Melanie; Colgan, Sean P.

doi:10.1096/fasebj.21.5.a131

Cited by 10 publications

(22 citation statements)

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“…These observations complete previous studies showing that mice lacking CD73 displayed increased colonic inflammation. 3,37 Our data using CD4-cre TGF-bRII lox/lox mice and vitamin A-deficient mice indicate that TGF-b and RA synergize to induce CD73 expression in Tconvs, whereas RA is dispensable for CD73 expression by Tregs. The source of RA is probably related to the population of CD103 þ dendritic cells in the LP 38,39 and to the MLN dendritic cells and stromal cell expressing aldh1a2, 40 a retinal dehydrogenase involved in the conversion of retinal into RA.…”

Section: Discussionmentioning

confidence: 90%

Intestinal immunopathology is associated with decreased CD73-generated adenosine during lethal infection

et al. 2015

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The ectonucleotidases CD39 and CD73 sequentially degrade the extracellular ATP pool and release immunosuppressive adenosine, thereby regulating inflammatory responses. This control is likely to be critical in the gastrointestinal tract where high levels of ATP are released in particular by commensal bacteria. The aim of this study was therefore to evaluate the involvement of the adenosinergic regulation in the intestine of mice in steady-state conditions and on acute infection with Toxoplasma gondii. We show that both conventional (Tconv) and regulatory (Treg) CD4(+) T lymphocytes express CD39 and CD73 in the intestine of naive mice. CD73 expression was downregulated during acute infection with T. gondii, leading to impaired capacity to produce adenosine. Interestingly, the expression of adenosine receptors was maintained and treatment with receptor agonists limited immunopathology and dysbiosis, suggesting that the activation of adenosine receptors may constitute an efficient approach to control intestinal inflammation associated with decreased ectonucleotidase expression.

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Section: Discussionmentioning

confidence: 90%

Intestinal immunopathology is associated with decreased CD73-generated adenosine during lethal infection

et al. 2015

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“…As proof of principle for the relevance of ␤1-integrin induction in vivo, we investigated ITGB1 expression in the TNBS murine model of colitis, a model we have previously shown to result in severe ulceration and concomitant tissue hypoxia (25). Moreover, as an extension of our previous work (21) implicating PHD inhibition and enhanced reepithelialization of colitic wounds (Fig.…”

Section: Itgb1 Is Induced In a Murine Model Of Colitismentioning

confidence: 93%

“…The transcriptional profile of T84 epithelial cells subjected to control (normoxia, pO 2 147 torr) or hypoxia (pO 2 20 torr for 6 or 18 h hypoxia) was assessed from total RNA using quantitative genechip expression arrays (Affymetrix, Santa Clara, CA, USA) (25). Results obtained by gene array analysis were subsequently verified in 18CO human fibroblast cells by real-time polymerase chain reaction (PCR) (ITGB1 primer set: forward, 5Ј-CCTTGG-GATGACTTGATTG-3Ј; reverse, 5Ј-ACCTTTCGGTCACTTAG-GG-3Ј) using iQ SYBR mix (iCycler; Bio-Rad, Hercules, CA, USA), as described previously (25,26).…”

Section: Transcriptional Analysismentioning

confidence: 99%

Selective induction of integrin βi by hypoxia‐inducible factor: implications for wound healing

et al. 2008

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Because of localized vascular damage and increased tissue oxygen demand, wound healing occurs in a relatively hypoxic microenvironment. These features are particularly relevant to wound healing and fibrosis in chronic inflammatory conditions, such as Crohn's disease and ulcerative colitis. In these studies, we sought to identify the contribution of hypoxia to mechanisms of wound repair in a model of the intestinal submucosa. Initial studies revealed that hypoxia promotes wound healing, as modeled by an increase in intestinal fibroblast-mediated collagen gel contraction. Guided by results from transcriptional profiling, we identified the selective induction of fibroblast integrin beta1 (ITGB1) by hypoxia. Further analysis revealed that hypoxia, as well as pharmacological activators of hypoxia-inducible factor (HIF), induce fibroblast beta1 integrin mRNA, protein, and function by as much as 4-fold. Cloning and analysis of the beta1 integrin gene promoter revealed a 10 +/- 0.8-fold increase in promoter activity in response to hypoxia, and subsequent studies identified a functional DNA binding region for HIF in the ITGB1 gene promoter. Mutational analysis of the HIF binding site within the ITGB1 promoter resulted in a significant loss of ITGB1 hypoxia-inducibility. As proof of principle, studies in a murine model of colitis revealed a correlation between colitic disease severity and tissue ITGB1 expression (R(2)=0.80). Taken together, these results demonstrate that hypoxia induces fibroblast ITGB1 expression and function by transcriptional mechanisms dependent on HIF.

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“…However, a seminal paper from our lab provides some evidence linking HIF1-dependent CD73 expression and type I IFN production in inflamed intestinal tissues. Gene array profiling performed on colonic mucosal scrapings of CD73-/-vs. wild-type mice revealed a loss of IFNαA expression in the absence of CD73 [25]. It appears that while type I IFNs induce CD73 expression, the activity of CD73, in turn, functions in a feed-forward manner to drive IFNαA expression.…”

Section: Cd73 Ifnαa and Colitismentioning

confidence: 95%

“…Meanwhile, additional reports of studies in murine models of colitis have indicated a protective role for the Ado A3R [23,24]. Thus, lack of Ado in a setting of intestinal inflammation may be detrimental and, indeed, as it was shown in CD73-/-mice impaired in Ado production, the absence of Ado leads to exacerbation of colitis [25].…”

Section: Ado Signalingmentioning

confidence: 99%

CD73-Dependent Regulation of Interferon AlphaA and Interleukin-10 in the Inflamed Mucosa

Sotnikov

Louis

2010

The Scientific World JOURNAL

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The ecto-5'-nucleotidase, CD73, catalyzes the rate-limiting step in the phosphohydrolysis of ATP to adenosine, and is a critical regulator of the balance between adenosine and its nucleotide precursors. Each of these classes of mediators signal through their independent receptor families to regulate downstream inflammatory signaling. CD73 activity is primarily regulated at the level of transcription in response to the oxygen-sensing transcription factor HIF1, and its tissue-specific expression correlates negatively with oxygen tension. HIF1-dependent induction of CD73 contributes to the protective effects of hypoxia in the inflamed intestinal mucosa. These beneficial effects of CD73 have largely been attributed to downstream adenosine signaling through its tissue-specific receptors. In addition, adenosine signaling has been directly implicated in the protective effects of hypoxic preconditioning against acute hypoxic or ischemic insults. However, recent work has demonstrated that CD73-/- animals lack the ability to produce interferon (IFN) αA, either at baseline or in response to inflammation. Furthermore, this IFN-αA deficiency is associated with the inability to elaborate interleukin (IL)-10–dependent anti-inflammatory signaling. It remains unclear whether interruption of IFN-αA and IL-10 signaling in the absence of CD73 activity results from a deficiency of its product adenosine or an accumulation of its substrate nucleotides. Current evidence for adenosine- and nucleotide-mediated mechanisms of tissue inflammation is reviewed below (Fig. 1).

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Control of Interferon‐alphaA by CD73: Implications for Mucosal Inflammation

Cited by 10 publications

References 0 publications

Intestinal immunopathology is associated with decreased CD73-generated adenosine during lethal infection

Intestinal immunopathology is associated with decreased CD73-generated adenosine during lethal infection

Selective induction of integrin βi by hypoxia‐inducible factor: implications for wound healing

CD73-Dependent Regulation of Interferon AlphaA and Interleukin-10 in the Inflamed Mucosa

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