Sirtuin 1 (SIRT1) belongs to class 3 histone deacetylase (HDAC3) with a role in differentiating and activating dendritic cells (DCs)

Author(s)

Jean de Lima

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2021-01-11

Examining board members

Niels Olsen Saraiva Câmara; Jose Alexandre Marzagao Barbuto; Thiago Andrade Patente; Patricia Torres Bozza Viola

• Advisor: Niels Olsen Saraiva Câmara; Vinicius de Andrade Oliveira

Abstract

Therefore, by modulating transcription factors, cytoplasmic proteins and metabolism components, SIRT1 can control the functions of DCs and the polarization and activation of T lymphocytes. Our hypothesis was that obesity would influence the expression of SIRT1 in DCs, changing its phenotype and function and, consequently, activation of CD4 &#43 T cells, which would exacerbate the inflammatory response in obesity. We observed that DCs derived from bone marrow, secondary lymphoid organs and visceral adipose tissue from obese animals had less expression and, in BMDCs from obese animals, SIRT1 activity was reduced when compared to BMDCs from lean animals. The absence of SIRT1 expression in the DCs of obese animals had an impact on mitochondrial metabolism, and the inhibition of SIRT1 reduced OXPHOS and increased ECAR, in contrast to the treatment with Resveratrol which promoted an opposite effect. The reduction in SIRT1 increased the expression of MHC-II, CD86 and CD40, increased the production of IL-12p40 and decreased the production of TGF-, culminating in greater polarization of CD4 &#43 T cells to the Th1 subtype. The increase in SIRT1 in DCs induced a polarization of T lymphocytes to a regulatory profile (CD25 &#43 Foxp3 &#43). Corroborating these data, animals selectively devoid of SIRT1 in DCs (SIRT1), submitted to the diet-induced obesity model, had greater insulin resistance and less glucose tolerance. These changes were correlated with an increase in the amount of visceral fat (VAT) of the SIRT1 animals and a lower frequency of DCs of the cDC1 subtype and greater of cDC2. In addition, the Kynurenine pathway was reduced in obese animals, especially in the absence of SIRT1. Finally, we identified that SIRT1 positively regulates the expression of Ido1. Therefore, the present study identified that SIRT1 controls the metabolism and functions of DCs, via modulation of the Kynurenine pathway and IDO1, phenotypes most impacted in obesity. The SIRT1-IDO1 axis may be a new target in the treatment of chronic inflammation present in obesity and associated comorbidities. (AU)

• FAPESP's process: 18/04326-1 - The role of sirtuin 1 in the phenotype and function of dendritic cells in the context of organ transplantation in obese animals
• Grantee: Jean de Lima
• Support Opportunities: Scholarships in Brazil - Master