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From the Cover: CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease.

ABSTRACT: CD39/ENTPD1 hydrolyzes proinflammatory nucleotides to generate adenosine. As purinergic mediators have been implicated in intestinal inflammation, we hypothesized that CD39 might protect against inflammatory bowel disease. We studied these possibilities in a mouse model of colitis using mice with global CD39 deletion. We then tested whether human genetic polymorphisms in the CD39 gene might influence susceptibility to Crohn's disease. We induced colitis in mice using Dextran Sodium Sulfate (DSS). Readouts included disease activity scores, histological evidence of injury, and markers of inflammatory activity. We used HapMap cell lines to find SNPs that tag for CD39 expression, and then compared the frequency of subjects with high vs. low CD39-expression genotypes in a case-control cohort for Crohn's disease. Mice null for CD39 were highly susceptible to DSS injury, with heterozygote mice showing an intermediate phenotype compared to wild type (WT). We identified a common SNP that tags CD39 mRNA expression levels in man. The SNP tagging low levels of CD39 expression was associated with increased susceptibility to Crohn's disease in a case-control cohort comprised of 1,748 Crohn's patients and 2,936 controls (P = 0.005-0.0006). Our data indicate that CD39 deficiency exacerbates murine colitis and suggest that CD39 polymorphisms are associated with inflammatory bowel disease in humans.

SUBMITTER: Friedman DJ

PROVIDER: S-EPMC2757811 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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From the Cover: CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease.

Friedman David J DJ Künzli Beat M BM A-Rahim Yousif I YI Sevigny Jean J Berberat Pascal O PO Enjyoji Keiichi K Csizmadia Eva E Friess Helmut H Robson Simon C SC

Proceedings of the National Academy of Sciences of the United States of America 20090928 39

CD39/ENTPD1 hydrolyzes proinflammatory nucleotides to generate adenosine. As purinergic mediators have been implicated in intestinal inflammation, we hypothesized that CD39 might protect against inflammatory bowel disease. We studied these possibilities in a mouse model of colitis using mice with global CD39 deletion. We then tested whether human genetic polymorphisms in the CD39 gene might influence susceptibility to Crohn's disease. We induced colitis in mice using Dextran Sodium Sulfate (DSS) ...[more]

PMID: 19805374

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Project description:Purinergic signaling is important in the activation and differentiation of macrophages, which play divergent roles in the pathophysiology of liver fibrosis. The ectonucleotidase CD39 is known to modulate the immunoregulatory phenotype of macrophages, but whether this specifically impacts cholestatic liver injury is unknown. Here, we investigated the role of macrophage-expressed CD39 on the development of biliary injury and fibrosis in a mouse model of sclerosing cholangitis. Myeloid-specific CD39-deficient mice (LysMCreCd39fl/fl) were generated. Global CD39 null (Cd39-/-), wild-type (WT), LysMCreCd39fl/fl, and Cd39fl/fl control mice were exposed to 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to induce biliary fibrosis. Hepatic hydroxyproline levels, liver histology, immunohistochemistry, mRNA expression levels, and serum biochemistry were then assessed. Following 3 weeks of DDC-feeding, Cd39-/- mice exhibited more severe fibrosis, when compared to WT mice as reflected by morphology and increased liver collagen content. Myeloid-specific CD39 deletion in LysMCreCd39fl/fl mice recapitulated the phenotype of global Cd39-/-, after exposure to DDC, and resulted in similar worsening of liver fibrosis when compared to Cd39fl/fl control animals. Further, DDC-treated LysMCreCd39fl/fl mice exhibited elevated serum levels of transaminases and total bilirubin, as well as increased hepatic expression of the profibrogenic genes Tgf-β1, Tnf-α, and α-Sma. However, no clear differences were observed in the expression of macrophage-elaborated specific cytokines between LysMCreCd39fl/fl and Cd39fl/fl animals subjected to biliary injury. Our results in the DDC-induced biliary type liver fibrosis model suggest that loss of CD39 expression on myeloid cells largely accounts for the exacerbated sclerosing cholangitis in global CD39 knockouts. These findings indicate that macrophage expressed CD39 protects from biliary liver injury and fibrosis and support a potential therapeutic target for human hepatobiliary diseases.

Project description:A major component of aging is chronic, low-grade inflammation, attributable in part by impaired gut barrier function. We previously reported that deletion of ghrelin, a peptidergic hormone released mainly from the gut, exacerbates experimental muscle atrophy in aged mice. In addition, ghrelin has been shown to ameliorate colitis in experimental models of inflammatory bowel disease (IBD), although the role of endogenous ghrelin in host-microbe interactions is less clear. Here, we showed that 22-month-old global ghrelin knockout (Ghrl-/-) mice exhibited significantly increased depressive-like behaviors, while anxiety levels and working memory were similar to littermate wild-type (WT) mice. Furthermore, old Ghrl-/- mice showed significantly increased intestinal permeability to fluorescein isothiocyanate (FITC)-dextran, significantly higher colonic interleukin (IL-1β) levels, and trends for higher colonic IL-6 and tumor necrosis factor-α (TNF-α) compared to WT mice. Interestingly, young Ghrl-/- and WT mice showed comparable depressive-like behavior and gut permeability, suggesting age-dependent exacerbation in gut barrier dysfunction in Ghrl-/- mice. While fecal short-chain fatty acids levels were comparable between old Ghrl-/- and WT mice, serum metabolome revealed alterations in metabolic cascades including tryptophan metabolism. Specifically, tryptophan and its microbial derivatives indole-3-acetic acid and indole-3-lactic acid were significantly reduced in old Ghrl-/-mice. Furthermore, in an experimental model of dextran sulfate sodium (DSS)-induced colitis, Ghrl-/- mice showed exacerbated disease symptoms, and higher levels of chemoattractant and pro-inflammatory cytokines in the colon. Overall, these data demonstrated that ghrelin deficiency is associated with gut barrier dysfunction, alterations in microbially derived tryptophan metabolites, and increased susceptibility to colitis. These data suggested that endogenous ghrelin contributes to maintaining a healthy host-microbe environment, ultimately impacting on brain function.

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From the Cover: CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease.

Publications

From the Cover: CD39 deletion exacerbates experimental murine colitis and human polymorphisms increase susceptibility to inflammatory bowel disease.

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