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

Chagas disease, caused by Trypanosoma cruzi, stands as the primary cause of dilated cardiomyopathy in the Americas. Macrophages play a crucial role in the heart's response to infection. Given their functional and phenotypic adaptability, manipulating specific macrophage subsets could be vital in aiding essential cardiovascular functions including tissue repair and defense against infection. PPARα are ligand-dependent transcription factors involved in lipid metabolism and inflammation regulation. However, the role of fenofibrate, a PPARα ligand, in the activation profile of cardiac macrophages as well as its effect on the early inflammatory and fibrotic response in the heart remains unexplored. The present study demonstrates that fenofibrate significantly reduces not only the serum activity of tissue damage biomarker enzymes (LDH and GOT) but also the circulating proportions of pro-inflammatory monocytes (CD11b⁺ LY6C^high). Furthermore, both CD11b⁺ Ly6C^low F4/80^high macrophages (MΦ) and recently differentiated CD11b⁺ Ly6C^high F4/80^high monocyte-derived macrophages (MdMΦ) shift toward a resolving phenotype (CD206^high) in the hearts of fenofibrate-treated mice. This shift correlates with a reduction in fibrosis, inflammation, and restoration of ventricular function in the early stages of Chagas disease. These findings encourage the repositioning of fenofibrate as a potential ancillary immunotherapy adjunct to antiparasitic drugs, addressing inflammation to mitigate Chagas disease symptoms.