Fenofibrate Induces a Resolving Profile in Heart Macrophage Subsets and Attenuates Acute Chagas Myocarditis

Abstract

Chagas disease, caused by Trypanosoma cruzi, stands as the primary causeof dilated cardiomyopathy in the Americas. Macrophages play a crucial role in the heart’sresponse to infection. Given their functional and phenotypic adaptability, manipulatingspecific macrophage subsets could be vital in aiding essential cardiovascular functionsincluding tissue repair and defense against infection. PPARα are ligand-dependenttranscription factors involved in lipid metabolism and inflammation regulation. However,the role of fenofibrate, a PPARα ligand, in the activation profile of cardiac macrophages aswell as its effect on the early inflammatory and fibrotic response in the heart remainsunexplored. The present study demonstrates that fenofibrate significantly reduces not onlythe serum activity of tissue damage biomarker enzymes (LDH and GOT) but also thecirculating proportions of pro-inflammatory monocytes (CD11b+ LY6Chigh). Furthermore,both CD11b+ Ly6Clow F4/80high macrophages (MΦ) and recently differentiated CD11b+Ly6Chigh F4/80high monocyte-derived macrophages (MdMΦ) shift toward a resolvingphenotype (CD206high) in the hearts of fenofibrate-treated mice. This shift correlates witha reduction in fibrosis, inflammation, and restoration of ventricular function in the earlystages of Chagas disease. These findings encourage the repositioning of fenofibrate as apotential ancillary immunotherapy adjunct to antiparasitic drugs, addressing inflammationto mitigate Chagas disease symptoms.