Fenofibrate increases the population of non-classical monocytes in asymptomatic Chagas disease patients and modulates inflammatory cytokines in PBMC

FEDERICO N PENAS; MONICA GILI; GOREN, NORA; ÁGATA CAROLINA CEVEY; ANA MORI; JUAN GAGLIARDI; PIERALISI, AZUL VICTORIA; NILDA PRADO; GERARDO ARIEL MIRKIN

Frontiers in Cellular and Infection Microbiology

Frontiers Media

Lugar: Lausanne; Año: 2022

Chronic chagasic 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 (PBMCs) infiltrate the tissue anddifferentiate into inflammatory macrophages. Advances in pathophysiology show that myeloid cell subpopulations contribute tocardiac 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 investigatedthe spontaneous release of inflammatory cytokines and chemokines, changes in the frequencies of monocyte subsets andfenofibrate effects on PBMCs of seropositive patients with different clinical stages of Chagas disease. The results show that PBMCsfrom 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 ofpro-inflammatory mediators and CCR2 in both Asy and CHD patients. We found that CHD patients display a significantly higherpercentage of classical monocytes in comparison with Asy patients and HI. Besides, Asy patients have a significantly higherpercentage of non-classical monocytes than CHD or HI. However, no difference in the intermediate monocyte subpopulation wasfound between groups. Moreover, monocytes from Asy or CHD patients exhibit different responses upon stimulation in vitro withT. cruzi lysates and fenofibrate treatment. Stimulation with T. cruzi significantly increases the percentage of classical monocytes inthe Asy group, the percentage of intermediate monocytes decreases. Besides, there are no changes in their frequencies in CHD orHI. Notably, stimulation with T. cruzi did not modify the frequency of the non-classical monocytes subpopulation in any of the groupsstudied. Moreover, fenofibrate treatment of T. cruzi-stimulated cells, increased even more the frequency of the non-classicalsubpopulation in Asy patients. Interestingly, fenofibrate restores CCR2 levels but does not modify HLA-DR expression in all groups ofpatients. In conclusion, our results emphasize a potential role for fenofibrate as modulator of monocyte subpopulations towards ananti-inflammatory and healing profile in different stages of chronic Chagas disease.