Bilirubin suppresses Th17 immunity in colitis by upregulating CD39
Maria Serena Longhi, … , Francisco J. Quintana, Simon C. Robson
Maria Serena Longhi, … , Francisco J. Quintana, Simon C. Robson
Published May 4, 2017
Citation Information: JCI Insight. 2017;2(9):e92791. https://doi.org/10.1172/jci.insight.92791.
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Research Article Gastroenterology Immunology

Bilirubin suppresses Th17 immunity in colitis by upregulating CD39

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.

Authors

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

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Figure 4

Failure of UCB immunoregulatory properties in Entpd1–/– mice.

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Failure of UCB immunoregulatory properties in Entpd1–/– mice. Entpd1–/– ...
Entpd1–/– mice (n = 12) were given 3% DSS for 8 days and then normal water for additional 4 days. For the whole duration of the experiment, mice were administered either vehicle (n = 6) or UCB (n = 6) at 20 μmol/kg/day. (A) Mean ± SEM disease activity index in vehicle- and UCB-treated Entpd1–/– mice. (B) Mean ± SEM colon length (cm) at the time of harvesting. (C) H&E staining of colon sections (original magnification, ×10); arrows indicate the area magnified in the insets (×20); mean ± SEM histology score at the time of harvesting is also shown. (D) Mean ± SEM frequency of CD4+IL-17+, CD4+IL-10+, and CD4+IL-17+IL-10+ cells among mononuclear cells obtained from spleen, MLNs, and from IELs and LPs of Entpd1–/– mice. (E) Mean ± SEM frequency of CD4+CD39+ lymphocytes in WT mice. (F) Mean ± SEM relative Entpd1 mRNA expression in the total lymphocyte fraction obtained from spleen and IELs. Data are representative of 1 of 3 independent experiments. P values derived using paired t test. *P ≤ 0.05. nd: not done. DSS, dextran sodium sulfate; UCB, unconjugated bilirubin; MLNs, mesenteric lymph nodes; IELs, intraepithelial lymphocytes; LPs, lamina propria lymphocytes.