Study of the Role of LXR receptors in the differentiation of TCD4 cells In-vitro and In-vivo

Author(s)

Juliana Edelvacy Lima Pinto

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Ciências Biomédicas (ICB/SDI)
• Defense date: 2023-03-27

Examining board members

Pedro Manoel Mendes de Moraes Vieira; Alexandre de Castro Keller; Luiz Osório Silveira Leiria; Maria Regina D'Imperio Lima

• Advisor: Pedro Manoel Mendes de Moraes Vieira

Abstract

LXRs (liver x receptors) are nuclear receptors that act as sensors of the bodys cholesterol levels, playing a crucial role in the regulation of the metabolism, transport, and efflux of lipids. LXRs are found in two isoforms, LXRα e LXRß, where the expression of LXR is primarily in the intestine, liver, and adipose tissue, while LXRß is expressed in almost all cell types. In response to the association with a ligand, LXRs become active and translocate to the nucleus, where, in association with a retinoid receptor (RXR), act as gene expression modulators and as well as a regulator of the metabolism and cholesterol efflux. In addition to its function on the regulation of the metabolism homeostasis, LXRs also participate in inflammatory regulation, with an anti-inflammatory role, due to its capacity of inhibiting NF-Kb activation, which occurs through a mechanism called trans repression that involves the binding to a peptide called SUMO. Although many works have described the benefic effects of LXR activation for the regulation of the inflammatory response, little is known of the SUMOylation effects of LXRs in the polarization of T CD4+ cells. Thus, the aim of this work is to understand how the two LXR isoforms act on TCD4+ lymphocyte polarization. We observed a reduction in the polarization of Th1, Treg and Th17 lymphocytes when both receptors are deleted, but with a more evident effect upon LXRß deletion. LXR has an anti-inflammatory effect when activated with agonists GW3965, while its inhibition through the use of antagonist PFG2 has a pro-inflammatory effect. Both isoforms are important for this effetcs. We also observed a reduced expression of GLUT1 and activation of NF-kb when both isoforms are deleted. Despite the effects observed, we found that in vivo that LXR deletion increased the production of pro-inflammatory cytokines from T CD4 cells. Thus, it is evident that the two isoforms of LXRs have an essential role in T CD4 lymphocyte polarization, with an even more evident role for LXRß. (AU)

• FAPESP's process: 20/16626-0 - Study of the role of LXR receptor SUMOylation in the differentiation of T CD4 lymphocytes
• Grantee: Juliana Edelvacy Lima Pinto
• Support Opportunities: Scholarships in Brazil - Master