Abstract

Role of Sirtuin 1 in the phenotype and functions of dendritic cells in the context of transplantation of obese animals

Author(s): Jean de Lima

Sirtuin 1 (SIRT1) is a class 3 Histone Deacetylase (HDAC3) that acts primarily by regulating T cell differentiation, proliferation and activation, therefore disable transcriptions of genes in Dendritc Cells (DCs) that are important for T cell activation and differentiation of effector cells in graft rejection and in other chronic infl ammatory processes like obesity. Therefore, our hypothesis that the obesity infl uences the differential expression of sirtuin 1 (SIRT1) in DCs, changing its phenotype and function, and thus T cell activation, exacerbating the allograft immune response. Thus, our goal was to specifi cally investigate the role of SIRT1 in the function, phenotype and the implications on DCs metabolism, and if it can affect T cell functions in the context of skin transplantation in obese animals. We saw the impact of absence of SIRT1 in the mitochondrial metabolism of DCs (by Seahorse technology) in animals with specifi c deletion of SIRT1 gene in DCs (CD11cCreSIRT1fl ox/fl ox). In addtion, we observed after treatment with a SIRT1 agonist (resveratrol, 50 nM) in Bone Marrow-Derived DC (BMDCs) incresead of protein expression of TGF-β, IDO and the decreased of costimulatory molecules (CD40, CD80, CD86) with parallel induction of SIRT1. In a hyperlipid diet-induced obesity (HFD) mode plus tranplantation, we observed that DCs from obese animals and with skin graft had the most lower SIRT1 expression and this led to a more pro-infl amatory profi le as well as less glycolytic metabolic profi le and relation with tryptophan metabolism, which is characteristic of a DC tolerance according to the literature. Based on the results obtained so far, we can suggest that increased expression of SIRT1 by resveratrol treatment leads to a more tolerogenic profi le in BMDCs and DC, which may infl uence CD4+ T cell proliferation and polarization and consequently an improvement in the graft acceptance in obesity