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Role of Short-Chain Fatty Acids and Ffar2 in Dendritic Cell Metabolism and Function
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Orientador(es)
Resumo(s)
Dendritic Cells (DCs) play a pivotal role in the regulation of the immune system, acting as a conduit
between innate and adaptive immunity by presenting antigens to naïve T cells. Research has
demonstrated that Short Chain Fatty Acids (SCFAs), particularly butyrate, significantly regulate immune
responses. This project aims to examine the role of butyrate in DC activation and function, as well as its
potential in promoting immune tolerance, particularly through its interaction with regulatory T (Treg)
cells. Bone marrow-derived progenitors from mice were cultured with the growth factor FMS-like
Tyrosine Kinase (FLT3-L) alone or in combination with Granulocyte-Macrophage Colony-Stimulating
Factor (GM-CSF) and exposed to varying butyrate concentrations. Flow Cytometry (FACS) enabled the
acquisition of data on DC composition and activation, focusing on the expression of several surface
markers. Western Blot (WB) was conducted to assess butyrate’s impact on acetylation. RT-qPCR was
employed to examine the gene expression associated with anti-inflammatory cytokines, DC metabolism
enzymes, and SCFA receptors, all linked to immune tolerance. Co-culture experiments assessed the
influence of butyrate pre-treated DCs on Foxp3+ Treg cell differentiation from naïve CD4+ T cells.
Results demonstrate that butyrate influences DC activation and functionality. Increased CD86
expression in iCD103-DC cultures and CD80 expression in FLT3-L DC cultures suggest that butyrate
modulates different activation pathways depending on the cell type. Butyrate induced a tolerogenic
profile in LPS-induced DCs, resulting in reduced IL-12 and TNF-α at gene and protein levels. WB
confirmed butyrate inhibits histone deacetylases (HDACs), resulting in increased acetylation of histone
3 (H3) and other proteins. This may be associated with changes in gene expression that favour a
tolerogenic environment. In the co-culture experiments, DCs treated with butyrate exhibited enhanced
efficacy in inducing Treg cells, indicating that butyrate conditions DCs to promote immune tolerance.
These findings suggest that butyrate profoundly influences immune responses.
Descrição
Tese de mestrado, Bioquímica e Biomedicina, 2024, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Células Dendríticas Células T Regulatórias Ácidos Gordos de Cadeira Curta Butirato Ffar2 Teses de mestrado - 2024