SIRT1 enhances Th17 cell generation by deacetylating RORγt (P1163)

Abstract

Abstract Although Sirtuin 1 (SIRT1), an NAD-dependent protein deacetylase, has emerged as a critical regulator of the cell cycle, replicative senescence, inflammation, and metabolism, its contribution to immune function remains to be fully investigated. Here we report that SIRT1 regulates the function of IL-17 producing CD4 T helper cells (Th17 cells) by modulating the activity of the Th17 master transcription factor RORγt. We found that Sirt1 interacts with RORγt and increases its transcriptional activity by deacetylating lysine residues K16 and K81. In mixed hematopoietic chimeras, cells from donors in which Sirt1 is deleted in ROR γ+ cells (SIRT1-cKO) exhibited compromised Th17 differentiation. Moreover, SIRT1-cKO mice were resistant to developing experimental autoimmune encephalomyelitis (EAE) upon MOG peptide immunization. Importantly, the SIRT1 specific inhibitor Ex-527 substantially inhibited trans-differentiation to Th17 cells in vitro, and injection of Ex-527 into mice strongly blocked EAE disease progression in vivo. These findings reveal a previously unappreciated proinflammatory role of SIRT1 in CD4 T cells, and provide significant evidence that pharmacological SIRT1 inhibitors might constitute a novel approach in the treatment of Th17-mediated autoimmune diseases such as multiple sclerosis.