immunology of infectious and parasitic diseases - XXXVII Congress ...

PPAR-α AGONIST GEMFIBROZIL DECREASES SPLEEN TREG CELLS
AND AUGMENT MICE SUSCEPTIBILITY TO Toxoplasma gondii
INFECTION
GIULIANO BONFÁ (1) ; LUCIANA BENEVIDES (1) ; MONIQUE THAÍS COSTA
FONSECA (1) ; FRANCIELLE RODRIGUES GUIMARÃES (2) ; DENISE MORAIS
FONSECA (1) ; NEIDE MARIA SILVA (3) , JOÃO SANTANA SILVA (1) ; CRISTINA
RIBEIRO DE BARROS CARDOSO (2)
(1) Department of Biochemistry and Immunology - School of Medicine of
Ribeirao Preto - FMRP/USP - SP - Brazil; (2) Department of Clinical Analyses,
Toxicology and Food Sciences - School of Pharmaceutical Sciences of Ribeirao
Preto - FCFRP/USP - SP - Brazil; (3) Biomedical Science Institute - Federal
University of Uberlândia - ICB/UFU - MG - Brazil. E-mail: giubonfa@usp.br
Introduction: Peroxisome proliferator-activated receptors (PPARs) are nuclear
receptors of which PPARα is the most studied. PPARs function as lipid
sensors, regulating metabolism and immune response by acting as transcription
factor resulting in the inhibition of pro-inflammatory cytokines. Toxoplasma
gondii infection induces a robust Th1 inflammatory response similar to
Inflammatory Bowel Disease (IBD) with excessive IFN-γ, TNF and nitric oxide
(NO) production. The role of PPAR in the gut inflammation caused by T. gondii
in some mice lineages and its possible association with regulation of immune
response is still unclear. Then, the aim of this work was to evaluate the role of
activated PPAR-α in the susceptibility to T. gondii infection.
Methods and Results: C57BL/6 mice were orally infected with cysts of T.
gondii, ME-49 strain. The transcripts of PPAR-α were evaluated at 0, 4, 6 and 8
days post-infection (p.i.) by real time PCR (qPCR) of ileum and liver on mice
inoculated with 40 cysts. One group of animals infected with 5 cysts was treated
with PPAR-α agonist (Gemfibrozil, GEM) for mortality assessment, ileum and
liver histological evaluation. Spleen cells were phenotyped by flow cytometry.
PPAR-α expression was downregulated in ileum and liver at day 8 p.i. when
compared to the previous periods evaluated. Interestingly, when mice were
treated with GEM at 10mg/Kg/day for 7 days p.i. there was an increase in
mortality. Infection increased inflammatory infiltrate in the ileum associated with
visible edema at the villi in vehicle and GEM treated mice. However, GEM
group presented an intense inflammation with reduced length and larger villi.
Liver inflammatory infiltrate was also increased and more diffuse in GEM
treated mice. In addition, there was an increased in NK and NKT cells
frequency and decreased number of T CD8 and T regulatory cells
(CD4 + CD25 + Foxp3 + ) in the spleen of GEM treated mice.
Conclusion: These data indicate that PPAR-α is modulated by T. gondii
infection in susceptible mice. Besides its known anti-inflammatory function,
activation of this nuclear receptor led to increased susceptibility to parasite
induced intestinal damage associated to decreased splenic Treg cells. These