15-deoxyprostaglandin-j2 and Chagas-Disease

Trypanosoma cruzi, the etiological agent of Chagas' disease, induces a persistent inflammatory response. Macrophages are a first line cell phenotype involved in the clearance of infection. Upon parasite uptake, these cells increase inflammatory mediators like NO, TNF-α, IL-1β and IL-6, leading to parasite killing. Although desired, inflammatory response perpetuation and exacerbation may lead to tissue damage. Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent nuclear transcription factors that, besides regulating lipid and carbohydrate metabolism, have a significant anti-inflammatory effect. This is mediated through the interaction of the receptors with their ligands. PPARγ, one of the PPAR isoforms, has been implicated in macrophage polarization from M1, the classically activated phenotype, to M2, the alternatively activated phenotype, in different models of metabolic disorders and infection. In this study, we show for the first time that, besides PPARγ, PPARα is also involved in the in vitro polarization of macrophages isolated from T. cruzi-infected mice. Polarization was evidenced by a decrease in the expression of NOS2 and proinflammatory cytokines and the increase in M2 markers like Arginase I, Ym1, mannose receptor and TGF-β. Besides, macrophage phagocytic activity was significantly enhanced, leading to increased parasite load. We suggest that modulation of the inflammatory response by both PPARs might be due, at least in part, to a change in the profile of inflammatory macrophages. The potential use of PPAR agonists as modulators of overt inflammatory response during the course of Chagas' disease deserves further investigation.

Topics: Animals; Arginase; beta-N-Acetylhexosaminidases; Blotting, Western; Cells, Cultured; Chagas Disease; Cytokines; Host-Pathogen Interactions; Inflammation Mediators; Lectins; Ligands; Macrophage Activation; Macrophages; Male; Mice, Inbred BALB C; Microscopy, Fluorescence; Nitric Oxide Synthase Type II; Phagocytosis; PPAR alpha; PPAR gamma; Prostaglandin D2; Pyrimidines; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Transforming Growth Factor beta; Trypanosoma cruzi

The acute phase of Trypanosoma cruzi infection is associated with a strong inflammatory reaction in the heart characterised by a massive infiltration of immune cells that is dependent on the T. cruzi strain and the host response. 15d-PGJ(2) belongs to a new class of anti-inflammatory compounds with possible clinical applications. We evaluated the effects of 15d-PGJ(2) administered during the acute phase of T. cruzi infection in mice. Mice were infected with the Colombian strain of T. cruzi and subsequently treated with 15d-PGJ2 repeatedly for seven days. The inflammatory infiltrate was examined by histologic analysis. Slides were immunohistochemically stained to count the number and the relative size of parasite nests. Infection-induced changes in serum cytokine levels were measured by ELISA. The results demonstrated that treatment with 15d-PGJ(2) reduced the inflammatory infiltrate in the skeletal muscle at the site of infection and decreased the number of lymphocytes and neutrophils in the blood. In addition, we found that 15d-PGJ(2) led to a decrease in the relative volume density of amastigote nests in cardiac muscle. T. cruzi-infected animals treated with 15d-PGJ(2) displayed a statistically significant increase in IL-10 levels with no change in IFN-gamma levels. Taken together, we demonstrate that treatment with 15d-PGJ(2) in the acute phase of Chagas disease led to a controlled immune response with decreased numbers of amastigote nests, as measured by the volume density.

Topics: Animals; Chagas Disease; Enzyme-Linked Immunosorbent Assay; Immunity, Cellular; Immunohistochemistry; Interferon-gamma; Interleukin-10; Male; Mice; Mice, Inbred C57BL; PPAR gamma; Prostaglandin D2