The class III histone deacetylase sirtuin 1 in immune suppression and its therapeutic potential in rheumatoid arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic debilitating disease of the joints. Both the innate and adaptive immune responses participate in the development and progression of RA. While several therapeutic reagents, such as TNF-α agonists, have been successfully developed for the clinical use in the treatment of RA, more than half of the patients do not respond to anti-TNF therapy. Therefore, new therapeutic reagents are needed. Recent studies have shown that sirtuin 1 (Sirt1), a nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase, is a critical negative regulator of both the innate and adaptive immune response in mice, and its altered functions are likely to be involved in autoimmune diseases. Small molecules that modulate Sirt1 functions are potential therapeutic reagents for autoimmune inflammatory diseases. This review highlights the role of Sirt1 in immune regulation and RA.

Keywords: Epigenetic; Rheumatoid arthritis; Sirt1.

Fig. 1. A model of Sirt1 in T cell tolerance

A: recognition of self-antigen (Ag) by TCR in the absence of co-stimulation induces Sirt1 gene transcription through NFAT pathway. B: balanced TCR/CD28 signaling activates both AP-1 and NFAT to induce IL-2 production for T cell activation. Up-regulated Sirt1 inhibits AP-1 transcription to block the activation of tolerized T cells when they receive both TCR and CD28 stimuli.