title: Targeting sirtuin-1 alleviates experimental autoimmune colitis by induction of Foxp3+ T-regulatory cells.
abstract: Induced Forkhead box P3-positive (Foxp3(+)) T-regulatory cells (iTregs) are essential to gastrointestinal immune homeostasis, and loss of the ability to develop iTregs may lead to autoimmune colitis. We previously showed a role for sirtuin-1 (Sirt1) in control of Treg function and hypothesized that targeting of Sirt1 might enhance iTreg development and thereby represent a potential therapy for inflammatory bowel disease (IBD). We adoptively transferred CD4(+)CD25(-)Foxp3(-) T effector (TE) cells from wild-type (WT) (C57BL/6) or fl-Sirt1/CD4cre mice into B6/Rag1(-/-) mice and monitored the mice until they lost 10-15% of their weight. Adoptive transfer of TE cells lacking Sirt1 to B6/Rag1(-/-) mice resulted in a 2.8-fold increase in iTreg formation compared with mice receiving WT TE cells and correlated with attenuated colitis and reduced weight loss (1.04±1.4% vs. 13.97±2.2%, respectively, P<0.001). In a second model of IBD, we used pharmacologic Sirt1 targeting of mice receiving multiple cycles of dextran sodium sulfate (DSS) in their drinking water, alternated with fresh water. Likewise, WT mice receiving cyclic DSS and a Sirt1 inhibitor, EX-527, had reduced weight loss (5.8±5.9% vs. 13.2±6.9%, respectively, P=0.03) and increased iTreg formation compared with controls. Sirt1 appears a promising target for pharmacologic therapy of IBD as a result of promoting iTreg development.
authors.affiliation: Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: T
authors.initials: T
authors.lastname: Akimova
authors.affiliation: Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: H
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Bhatti
authors.affiliation: Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: J
authors.initials: J
authors.lastname: Jiao
authors.affiliation: Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: E
authors.initials: E
authors.lastname: Eruslanov
authors.affiliation: Department of Surgery, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: S
authors.initials: S
authors.lastname: Singhal
authors.affiliation: Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: L
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: R
authors.initials: R
authors.lastname: Han
authors.affiliation: Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: K
authors.initials: K
authors.lastname: Zacharia
authors.affiliation: Division of Transplant Immunology, Department of Pathology and Laboratory Medicine and Biesecker Center for Pediatric Liver Disease, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
authors.forename: W W
authors.initials: WW
authors.lastname: Hancock
authors.affiliation: Division of Nephrology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: U H
authors.initials: UH
authors.lastname: Beier
mesh_terms: D000818:Animals; D002227:Carbazoles / Q000494:pharmacology; D003093:Colitis, Ulcerative / Q000188:drug therapy* / Q000276:immunology; D016264:Dextran Sulfate / Q000494:pharmacology; D016503:Drug Delivery Systems; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D056564:Sirtuin 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
chemical_list: C550547:6-chloro-2,3,4,9-tetrahydro-1H-carbazole-1-carboxamide; D002227:Carbazoles; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D016264:Dextran Sulfate; D056564:Sirtuin 1