TY - JOUR
T1 - Bilirubin suppresses Th17 immunity in colitis by upregulating CD39
AU - Longhi, Maria Serena
AU - Vuerich, Marta
AU - Kalbasi, Alireza
AU - Kenison, Jessica E.
AU - Yeste, Ada
AU - Csizmadia, Eva
AU - Vaughn, Byron
AU - Feldbrugge, Linda
AU - Mitsuhashi, Shuji
AU - Wegiel, Barbara
AU - Otterbein, Leo
AU - Moss, Alan
AU - Quintana, Francisco J.
AU - Robson, Simon C.
N1 - Copyright:
This record is sourced from MEDLINE/PubMed, a database of the U.S. National Library of Medicine
PY - 2017/5/4
Y1 - 2017/5/4
N2 - 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.
AB - 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.
KW - Gastroenterology
KW - Immunology
UR - http://www.scopus.com/inward/record.url?scp=85041463854&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85041463854&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.92791
DO - 10.1172/jci.insight.92791
M3 - Article
C2 - 28469075
AN - SCOPUS:85041463854
VL - 2
JO - JCI insight
JF - JCI insight
SN - 2379-3708
IS - 9
ER -