The role of PPAR and receptors in the modulation of inflammatory response during Toxoplasma gondii infection

Author(s)

Giuliano Bonfá

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2014-12-17

Examining board members

Cristina Ribeiro de Barros Cardoso; José Roberto Mineo; Sonia Jancar Negro

• Advisor: Cristina Ribeiro de Barros Cardoso

Abstract

PPAR receptors (\"peroxissome proliferator-activated receptor\") are nuclear transcription factors that function as lipid sensors that regulate metabolism and immune response. They are expressed in T cells, macrophages, dendritic cells, epithelial cells and act by inhibiting inflammatory mediators such as IFNγ and nitric oxide (NO). The infection with T. gondii induces high inflammation, mainly of the type Th1, in order to eliminate the parasite. However, this response can lead to tissue damage and death of the host. Thus, PPAR receptors are promising targets for the control of inflammation caused by T. gondii or other inflammatory disorders. Then, in this work, the role of PPARα and γ in experimental infection by T. gondii was evaluated. The results showed that the T. gondii infection negatively modulated the expression of these receptors in both the liver and ileum. PPARα deficient mice or those treated with PPARγ agonist pioglitazone (PIO), were more susceptible to infection. The absence of PPARγ induced neutrophilia in mice with reduced frequency of CD8+ T cells in the spleen and NK in Peyer\'s patches. There was also a decrease in regulatory cells (CD4+CD25+Foxp3+ or PD1+) and increased production of IFNγ by CD4+ T spleen leukocytes. Treatment with PPARα agonist or antagonist in vitro resulted in a decrease of infected macrophages and NO production, besides a reduction in IL-10, IFNγ and NO by spleen cells. At the site of infection we observed increased parasitism in the distal jejunum, although there was no difference in the intestinal pathology comparing to C57BL/6 wild type mice. However, in the absence of PPARα there was elevated inflammation in the liver, which could have contributed to the increased susceptibility to infection. On the other hand, PPARγ activation did not influence the intestinal or liver injury in mice infected with T. gondii, neither the parasite burden nor cytokine production in these inflamed site. However, treatment with agonist or antagonist of this receptor, in vitro, led to modulation of effector mechanisms of macrophages and the activation of this molecule in spleen cells induced down regulation of IFNγ production. In addition, the control of this cytokine after infection was related to the activation of PPARγ in spleen and lymph node CD4 T cells, as seen in experiments using CD4-PPARγ -/- mice. Finally, these data provided evidences for the modulation caused by the activation of these receptors, generating new therapeutic perspectives for inflammatory disorders or lack of regulation via PPARs in mucosal immunity. (AU)

• FAPESP's process: 10/15518-7 - The role of PPAR-alpha and -gamma receptor in the modulation of inflammatory response during infection with Toxoplasma gondii
• Grantee: Giuliano Bonfá
• Support Opportunities: Scholarships in Brazil - Doctorate