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Published on: October 17, 2017
Fenofibrate Increases the Population of Non-Classical Monocytes in Asymptomatic Chagas Disease Patients and Modulates
Azul V Pieralisi1,2, Ágata C Cevey1,2, Federico N Penas1,2
1Universidad de Buenos Aires. Facultad de Medicina. Departamento de Microbiología, Parasitología e Inmunología, Buenos Aires, Argentina.
Insights
Fenofibrate reduces inflammatory mediators and modulates monocyte subsets in patients with chronic Chagas disease cardiomyopathy. This drug shows potential for treating Chagas heart disease by promoting anti-inflammatory and healing profiles in peripheral blood mononuclear cells.
Area of Science:
- Immunology
- Cardiology
- Pharmacology
Background:
- Chronic Chagas disease cardiomyopathy (CCC) is a severe complication of Trypanosoma cruzi infection.
- Peripheral blood mononuclear cells (PBMC) and their myeloid subpopulations play a role in CCC pathogenesis.
- Fenofibrate, a PPARα agonist, has shown therapeutic potential in preclinical models of Chagas disease.
Purpose of the Study:
- To investigate spontaneous inflammatory mediator release and monocyte subset frequencies in Chagas disease patients.
- To evaluate the effects of fenofibrate on PBMC from patients with asymptomatic or symptomatic Chagas disease.
- To explore fenofibrate's impact on monocyte responses to T. cruzi stimulation in vitro.
Main Methods:
- Analysis of cytokine and chemokine levels (IL-12, TGF-β, IL-6, MCP1) in PBMC from Chagas disease patients and healthy individuals.
- Flow cytometry to determine frequencies of monocyte subsets (classical, intermediate, non-classical).
- In vitro stimulation of patient-derived monocytes with T. cruzi lysates and fenofibrate treatment.
Main Results:
- Chagas disease patients exhibited elevated levels of IL-12, TGF-β, IL-6, MCP1, and CCR2 compared to healthy controls.
- Fenofibrate treatment reduced pro-inflammatory mediators and CCR2 levels in both asymptomatic and symptomatic patients.
- Significant differences in monocyte subset percentages were observed between asymptomatic, symptomatic, and healthy individuals, with distinct in vitro responses to T. cruzi and fenofibrate.
Conclusions:
- PBMC from Chagas disease patients show a pro-inflammatory profile, irrespective of clinical stage.
- Fenofibrate effectively modulates inflammatory mediators and monocyte subpopulations in Chagas disease.
- Fenofibrate holds promise as a therapeutic agent for managing inflammation and promoting healing in chronic Chagas disease.
Abstract:
Chronic Chagas disease cardiomyopathy (CCC) is the most important clinical manifestation of infection with Trypanosma cruzi (T. cruzi) due to its frequency and effects on morbidity and mortality. Peripheral blood mononuclear cells (PBMC) infiltrate the tissue and differentiate into inflammatory macrophages. Advances in pathophysiology show that myeloid cell subpopulations contribute to cardiac homeostasis, emerging as possible therapeutic targets. We previously demonstrated that fenofibrate, PPARα agonist, controls inflammation, prevents fibrosis and improves cardiac function in a murine infection model. In this work we investigated the spontaneous release of inflammatory cytokines and chemokines, changes in the frequencies of monocyte subsets, and fenofibrate effects on PBMC of seropositive patients with different clinical stages of Chagas disease. The results show that PBMC from Chagas disease patients display higher levels of IL-12, TGF-β, IL-6, MCP1, and CCR2 than cells from uninfected individuals (HI), irrespectively of the clinical stage, asymptomatic (Asy) or with Chagas heart disease (CHD). Fenofibrate reduces the levels of pro-inflammatory mediators and CCR2 in both Asy and CHD patients. We found that CHD patients display a significantly higher percentage of classical monocytes in comparison with Asy patients and HI. Besides, Asy patients have a significantly higher percentage of non-classical monocytes than CHD patients or HI. However, no difference in the intermediate monocyte subpopulation was found between groups. Moreover, monocytes from Asy or CHD patients exhibit different responses upon stimulation in vitro with T. cruzi lysates and fenofibrate treatment. Stimulation with T. cruzi significantly increases the percentage of classical monocytes in the Asy group whereas the percentage of intermediate monocytes decreases. Besides, there are no changes in their frequencies in CHD or HI. Notably, stimulation with T. cruzi did not modify the frequency of the non-classical monocytes subpopulation in any of the groups studied. Moreover, fenofibrate treatment of T. cruzi-stimulated cells, increased the frequency of the non-classical subpopulation in Asy patients. Interestingly, fenofibrate restores CCR2 levels but does not modify HLA-DR expression in any groups. In conclusion, our results emphasize a potential role for fenofibrate as a modulator of monocyte subpopulations towards an anti-inflammatory and healing profile in different stages of chronic Chagas disease.
