Targeting sirtuin-1 alleviates experimental autoimmune colitis by induction of Foxp3+ T-regulatory cells

Abstract

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.

Targeting Sirtuin-1 prolongs murine renal allograft survival and function

“…These data are add to our previous works that propose protolerogenic effects of Sirt1 targeting, especially in T cell dependent immunity. 16, 17 Mechanistically, Sirt1 has been identified as one of the histone/protein deacetylases that can deacetylate Foxp3, which reduces Foxp3 DNA binding and transcriptional regulatory efficiency, and also quickens the proteasomal turnover of Foxp3. 10–12 Kwon et al identified three lysine residues on Foxp3 (K31, K262, K267) that are deacetylated by Sirt1, leading to negative regulation of Treg number and function.…”

“…14 In contrast, Foxp3 − T cells retain the ability to proliferate and produce cytokines. 16, 17 However, CD4 + CD25 − conventional T cells are more susceptible to form de-novo induced Treg, both under polarizing conditions in cell culture as well as in vivo . 14, 16 Consistent with these data, we also find evidence of increased Foxp3 + Treg presence in the renal allograft tissue of Sirt1 fl/fl CD4 cre recipients.…”

“…16, 17 However, CD4 + CD25 − conventional T cells are more susceptible to form de-novo induced Treg, both under polarizing conditions in cell culture as well as in vivo . 14, 16 Consistent with these data, we also find evidence of increased Foxp3 + Treg presence in the renal allograft tissue of Sirt1 fl/fl CD4 cre recipients. Foxp3 + Tregs play an important role in suppressing allograft rejection, which has been demonstrated by induction of rejection through Treg ablation, 21 including in murine renal allograft models.…”

“…10–12, 14, 15 and we have previously shown that T cell-specific deletion–or pharmacologic inhibition–of Sirt1 can prolong cardiac allograft survival and suppress autoimmune colitis. 16, 17 …”

Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments

“…#160110, MP Biomedicals, Solon, OH), using a previously published chronic colitis model involving multiple repetitive cycles of 5% DSS designed to asses Th1 based immunopathology (Akimova et al, 2014; Okayasu et al, 1990). Briefly, 12-week-old female C57BL/6 mice (5 per group, randomly selected, and confirmed to have near equal starting weight with no significant difference between groups) received cycling doses of 5% DSS interchanged with normal drinking water every five to seven days (see Figure S6C for details), for a total observation period of 40 days.…”