Sirtuin-1 in immunotherapy: A Janus-headed target

Abstract

Sirtuin-1 (Sirt1), a member of the NAD-dependent sirtuin family of histone/protein deacetylases (HDAC), is an important target for immunotherapy due to its role in deacetylating the transcription factors Foxp3 and thymic retinoid acid receptor related orphan receptor gamma (RORγt). Sirt1 inhibition can increase Foxp3 acetylation and promote the production and functions of Foxp3⁺ T-regulatory (Treg) cells, whereas the acetylation of RORγt decreases its transcriptional activity DNA binding and decreases the differentiation of proinflammatory Th17 cells. Pharmacologic inhibitors of Sirt1 increase allograft survival and decrease autoimmune colitis and experimental allergic encephalomyelitis. However, in contrast to its role in T cells, Sirt1 has anti-inflammatory effects in myeloid cells, and, context dependent, in Th17 cells. Here, inhibition of Sirt1 can have proinflammatory effects. In addition to effects arising from the central role of Sirt1 in cellular metabolism and NAD-dependent reactions, such proinflammatory effects further complicate the potential of Sirt1 for therapeutic immunosuppression. This review aims to reconcile the opposing literature on pro- and anti-inflammatory effects of Sirt1, provides an overview of the role of Sir1 in the immune system, and discusses the pros and cons associated with inhibiting Sirt1 for control of inflammation and immune responses.

Keywords: Foxp3; T cells; Treg; immunosuppression; p65.

Figure 1:. Sirtuin-1 reaction and NAD recycling

Schematic showing Sirt1 reaction and NAD recycling. Sirt1 deacetylates ε-amino groups of lysine side chains in histones and many non-histone proteins, creating a positive charge. The acetylgroup is transferred to NAD, which has nicotinamide cleaved off, generating 2’- or 3’-O-acetyl ADP-ribose [23]. Sirt1 can use oxidized NAD, but not reduced NADH as co-factor. Nicotinamide is recycled to NAD through NAMPT and NMNAT. Several Sirt1 client proteins relevant to the immune system are indicated, which are either activated and stabilized (yellow) or destabilized (green) when Sirt1-dependent deacetylation is impaired. Abbreviations: NAD, nicotinamide adenine dinucleotide; NAM, nicotinamide; NMN, nicotinamide mononucleotide; NR, nicotinamide riboside; ATP, adenosine triphosphate; ADPR, adenosine diphosphate riboside; PRPP, phosphoribosyl pyrophosphate; PPi, inorganic pyrophosphate; K, lysine; NAMPT, Nicotinamide phosphoribosyltransferase; NMNAT, nicotinamide mononucleotide adenylyltransferase.

Figure 2:. Sirtuin-1 targeting in T cells and myeloid cells

Sirtuin-1 targeting has contrasting effects in myeloid and in T cells: In myeloid cells, p65 acetylation at lysine 310 leads to increased transcription of pro-inflammatory cytokines. In T cells, Foxp3 is stabilized by Sirtuin-1 inhibition due to increased lysine acetylation, which increases transcriptional activity and reduces proteasomal turnover. Foxp3 transcription is augmented by p65. In contrast to Foxp3, Rorγt is stabilized by Sirtuin-1 deacetylation, and thus, impaired with Sirtuin-1 inhibition, which aids in tilting the balance between pro-inflammatory Th17 and suppressive Treg cells. STAT3 can also be deacetylated (and destabilized) by Sirt1, which may explain that in some models, especially autoimmune uveitis, Sirt1 activation can suppress Th17 differentiation.