Sirtuin 1 regulates the phenotype and functions of dendritic cells through Ido1 pathway in obesity

Author(s):Show less -

de Lima, Jean ; Leite, Jefferson Antonio ; Basso, Paulo Jose ; Ghirotto, Bruno ; da Silva, Eloisa Martins ; Menezes-Silva, Luisa ; Hiyane, Meire Ioshie ; Goes, Carolina Purcell ; Coutinho, Luiz Lehmann ; Oliveira, Vinicius de Andrade ; Camara, Niels Olsen Saraiva

• Document type: Journal article
• Source: CELL DEATH & DISEASE; v. 15, n. 10, p. 17-pg., 2024-10-18.

Abstract

Sirtuin 1 (SIRT1) is a class III histone deacetylase (HDAC3) that plays a crucial role in regulating the activation and differentiation of dendritic cells (DCs) as well as controlling the polarization and activation of T cells. Obesity, a chronic inflammatory condition, is characterized by the activation of immune cells in various tissues. We hypothesized that SIRT1 might influence the phenotype and functions of DCs through the Ido1 pathway, ultimately leading to the polarization towards pro-inflammatory T cells in obesity. In our study, we observed that SIRT1 activity was reduced in bone marrow-derived DCs (BMDCs) from obese animals. These BMDCs exhibited elevated oxidative phosphorylation (OXPHOS) and increased extracellular acidification rates (ECAR), along with enhanced expression of class II MHC, CD86, and CD40, and elevated secretion of IL-12p40, while the production of TGF-beta was reduced. The kynurenine pathway activity was decreased in BMDCs from obese animals, particularly under SIRT1 inhibition. SIRT1 positively regulated the expression of Ido1 in DCs in a PPAR gamma-dependent manner. To support these findings, ATAC-seq analysis revealed that BMDCs from obese mice had differentially regulated open chromatin regions compared to those from lean mice, with reduced chromatin accessibility at the Sirt1 genomic locus in BMDCs from obese WT mice. Gene Ontology (GO) enrichment analysis indicated that BMDCs from obese animals had disrupted metabolic pathways, including those related to GTPase activity and insulin response. Differential expression analysis showed reduced levels of Pparg and Sirt1 in BMDCs from obese mice, which was challenged and confirmed using BMDCs from mice with conditional knockout of Sirt1 in dendritic cells (SIRT1 triangle). This study highlights that SIRT1 controls the metabolism and functions of DCs through modulation of the kynurenine pathway, with significant implications for obesity-related inflammation. (AU)

• FAPESP's process: 17/05264-7 - Cell metabolism, microbiota and immune system: new paradigms in renal diseases physiopathology
• Grantee: Niels Olsen Saraiva Câmara
• Support Opportunities: Research Projects - Thematic Grants
• 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
• FAPESP's process: 19/07820-0 - Sirtuins functions in lineages of conventional dendritic cells and IL-35 producing dendritic cell constitutively
• Grantee: Jean de Lima
• Support Opportunities: Scholarships abroad - Research Internship - Master's degree
• FAPESP's process: 23/07482-2 - Sensing extra and intracellular stressors by renal and immune cells: new insights into signal reception and transduction, and their relevance for understanding renal diseases
• Grantee: Niels Olsen Saraiva Câmara
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 19/19435-3 - The role of DNA damage and mitochondrial function in vascular, immune and neurological ageing (DNA MoVINg)
• Grantee: Carlos Frederico Martins Menck
• Support Opportunities: Research Projects - Thematic Grants