Bilirubin suppresses Th17 immunity in colitis by upregulating CD39

Maria Serena Longhi, Marta Vuerich, Alireza Kalbasi, Jessica E. Kenison, Ada Yeste, Eva Csizmadia, Byron Vaughn, Linda Feldbrugge, Shuji Mitsuhashi, Barbara Wegiel, Leo Otterbein, Alan Moss, Francisco J. Quintana, Simon C. Robson

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Unconjugated bilirubin (UCB), a product of heme oxidation, has known immunosuppressant properties but the molecular mechanisms, other than antioxidant effects, remain largely unexplored. We note that UCB modulates T helper type 17 (Th17) immune responses, in a manner dependent upon heightened expression of CD39 ectonucleotidase. UCB has protective effects in experimental colitis, where it enhances recovery after injury and preferentially boosts IL-10 production by colonic intraepithelial CD4+ cells. In vitro, UCB confers immunoregulatory properties on human control Th17 cells, as reflected by increased levels of FOXP3 and CD39 with heightened cellular suppressor ability. Upregulation of CD39 by Th17 cells is dependent upon ligation of the aryl hydrocarbon receptor (AHR) by UCB. Genetic deletion of CD39, as in Entpd1-/- mice, or dysfunction of AHR, as in Ahrd mice, abrogates these UCB salutary effects in experimental colitis. However, in inflammatory bowel disease (IBD) samples, UCB fails to confer substantive immunosuppressive properties upon Th17 cells, because of decreased AHR levels under the conditions tested in vitro. Immunosuppressive effects of UCB are mediated by AHR resulting in CD39 upregulation by Th17. Boosting downstream effects of AHR via UCB or enhancing CD39-mediated ectoenzymatic activity might provide therapeutic options to address development of Th17 dysfunction in IBD.

Original languageEnglish (US)
JournalJCI Insight
Volume2
Issue number9
DOIs
StatePublished - May 4 2017
Externally publishedYes

Keywords

  • Gastroenterology
  • Immunology

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    Longhi, M. S., Vuerich, M., Kalbasi, A., Kenison, J. E., Yeste, A., Csizmadia, E., Vaughn, B., Feldbrugge, L., Mitsuhashi, S., Wegiel, B., Otterbein, L., Moss, A., Quintana, F. J., & Robson, S. C. (2017). Bilirubin suppresses Th17 immunity in colitis by upregulating CD39. JCI Insight, 2(9). https://doi.org/10.1172/jci.insight.92791