Targeting Sirtuin-1 prolongs murine renal allograft survival and function

Abstract

Current immunosuppressive medications used after transplantation have significant toxicities. Foxp3+ T-regulatory (Treg) cells can prevent allograft rejection without compromising protective host immunity. Interestingly, inhibiting the class III histone/protein deacetylase Sirtuin-1 can augment Foxp3+ Treg suppressive function through increasing Foxp3 acetylation. Here we determined whether Sirtuin-1 targeting can stabilize biological allograft function. BALB/c kidney allografts were transplanted into C57BL/6 recipients with a CD4-conditional deletion of Sirtuin-1 (Sirt1fl/flCD4cre) or mice treated with a Sirtuin-1 specific inhibitor (EX-527), and the native kidneys removed. Blood chemistries and hematocrit were followed weekly. Sirt1fl/flCD4cre recipients showed markedly longer survival and improved kidney function. Sirt1fl/flCD4cre recipients exhibited donor specific tolerance, accepted BALB/c, but rejected third-party C3H cardiac allografts. C57BL/6 recipients of BALB/c renal allografts that were treated with EX-527 showed improved survival and renal function at 1, but not 10 mg/kg/day. Pharmacologic inhibition of Sirtuin-1 also improved renal allograft survival and function with dosing effects having relevance to outcome. Thus, inhibiting Sirtuin-1 can be a useful asset in controlling T-cell mediated rejection. However, effects on non-T cells that could adversely affect allograft survival and function merit consideration.

Sirtuin-1 in immunotherapy: A Janus-headed target

“…We later confirmed the observations by Lim et al. showing decreased Th17 polarization phenotype in Sirt1 fl/fl CD4 cre conventional CD4 + T cells . That said, Sirt1 also has been observed to interfere with Th17 development via deacetylation of signal transducer and activator of transcription (STAT)‐3, which is required for RORγt transcription .…”

“…This is especially relevant when Sirt1 inhibition is considered. For example, when using the Sirt1 inhibitor EX‐527 in MHC‐mismatched murine renal allografts, we noted that prolongation of allograft survival and function was present, though to a lesser extent than in mice with conditional deletion of Sirt in their T cells (Sirt1 fl/fl CD4 cre ), and was worsened upon increasing the dose of EX‐527 from 1 to 10 mg/kg/d . In addition to proinflammatory effects from innate immune cells, Sirt1 can aid protecting from ischemic injury, which is practically unavoidable during transplantation, and thus, the immunosuppressive treatment with EX‐527 may augment such injury.…”

“…To avoid confounding effects from Sirt1 deletion on thymic development, where Sirt1 plays a role on self‐tolerance, we mated Sirt1 fl/fl with CD4 cre and Foxp3 cre mice, generating mouse models bypassing the severe autoimmunity of global Sirt1 deletion, as well as using Sirt1 specific small molecule inhibitors . We observed that Sirt1 deletion and pharmacologic inhibition augmented Foxp3 + Treg function . In this review, we will discuss the role of Sirt1 in the immune system and its mechanism of action.…”

“…Foxp3 protein is post-translationally regulated by lysine acetylation through histone/protein deacetylases (HDACs) and histone acetyl transferases (HATs). 6 Global HDAC inhibition [7][8][9] or deletion of HDAC6, 9, 11 and Sirtuin-1 (Sirt1) [10][11][12][13][14][15][16][17] augments Treg function, whereas deleting HDAC3 or 5, Sirt3, or targeting the HATs p300 or CBP impairs Treg. [18][19][20][21][22] Sirtuins are class III HDACs, and stand out from the other HDAC families by being dependent on NAD as a co-factor ( Fig.…”

“…12 We observed that Sirt1 deletion and pharmacologic inhibition augmented Foxp3 + Treg function. [12][13][14][15] In this review, we will discuss the role of Sirt1 in the immune system and its mechanism of action. We will also address the practicality of therapeutically targeting Sirt1…”