Nicotinamide enhances Treg differentiation by promoting Foxp3 acetylation in immune thrombocytopenia.

Imbalanced nicotinamide adenine dinucleotide (NAD) homeostasis has been reported in multiple autoimmune diseases and supplementation with NAD precursors has consistently demonstrated positive therapeutic benefits for these conditions. Immune thrombocytopenia (ITP) is an acquired autoimmune disease, in which the decreased number and impaired function of regulatory T cells (Tregs) contribute to the main pathogenesis. Here we found NAD level was decreased in the plasma and CD4 T cells of ITP patients. Supplementation with NAD precursor nicotinamide (NAM), but not nicotinamide mononucleotide (NMN), increased Treg frequency and ameliorated thrombocytopenia in an ITP murine model. Moreover, whilst both NAM and NMN restored cytosolic NAD level in the CD4 T cells from ITP patients, only NAM promoted Treg differentiation. Mechanistically, Sirtuin1 (Sirt1), a major consumer of NAD, was highly expressed in the CD4 T cells of ITP patients, potentially contributing to the low level of NAD. NAM, which could act as Sirt1 inhibitor, promoted Foxp3 acetylation and stability in induced Tregs derived from naïve CD4 T cells of ITP patients. These findings suggest that NAM holds promise as a novel therapeutic strategy for restoring immune balance in ITP.