AhR and LXR transcriptional factors as targets to treat immune-mediated degenerative diseases

• Grant number: 19/04780-7
• Support type: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): November 10, 2019
• Effective date (End): November 09, 2020
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Pedro Manoel Mendes de Moraes Vieira
• Grantee: Jéssica Aparecida da Silva Pereira
• Supervisor abroad: Francisco Javier Quintana
• Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Local de pesquisa : Harvard University, Boston, United States
• Associated to the scholarship: 17/00079-7 - Effects of LXRs receptor activation on systemic metabolic parameters and on the metabolic modulation of resident tissue macrophages of adipose tissue, BP.DR

Abstract

Multiple sclerosis (MS) is considered a T-cell mediated autoimmune disease. Thus the study of the mechanisms that control the T cell response, as well as innovative strategies to modulate the pathways that control T-cell polarization by antigen-presenting cells (APCs) is likely to result in new therapeutic approaches. In this application we propose to study the mechanisms by which the transcription factors aryl hydrocarbon receptor (AHR) and liver X receptors (LXR) controls the APCs metabolism and the differentiation of effector and regulatory T cells, as well its potential as a therapeutic target. Recently, it was showed that AHR mediates the anti-inflammatory effects of IFNb in CNS inflammation. Moreover, AHR was recently shown to mediate the therapeutic effects of Laquinimod a new drug under development for the treatment of MS. Finally, AHR is one of the pathways involved in the modulation of CNS inflammation by the gut flora. In addiction, naringenin, a citrus-flavonoid molecule was showed to promote the inhibition of pro-inflammatory T cells and improve the degenerative effects in EAE model. We found that in macrophages naringenin is a LXR agonist. Also is reported that LXR activation may contribute to tolerogenic DCs and Treg cells generation. Thus, this proposal will shed light on the regulation of the MS-relevant immune processes by current disease modifying therapies for MS. Our studies will also illuminate the mechanisms used by environmental factors such as the gut flora to affect MS pathogenesis. Finally, these studies evaluate the therapeutic potential of transcriptional factors-targeted nanoparticles, an innovative approach that may represent a new method for the reestablishment of antigen-specific tolerance in MS, with minimal side effects. In conclusion, our studies have the potential to identify immunoregulatory pathways and new therapeutic approaches relevant for MS.