Targeting Sirtuin-1 Alleviates Experimental Autoimmune Colitis by Induction of Foxp3+ T-Regulatory Cells: Sirt1 targeting alleviates autoimmune colitis

Induced Foxp3(+) T-regulatory cells (iTreg) 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 (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 to mice receiving wild-type 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, wild-type mice receiving cyclic DSS and a Sirt1 inhibitor, EX-527, had reduced weight loss (5.8±5.9% vs. 13.2±6.9%, p=0.03) and increased iTreg formation compared to controls. Sirt1 appears a promising target for pharmacologic therapy of IBD as a result of promoting iTreg development.