Macrophages Mediate Healing Properties of Fenofibrate in Experimental Chagasic Cardiomyopathy

Abstract

Chronic cardiomyopathy is one of the most relevant outcomes of Chagas disease associated with parasite persistence and exacerbated inflammatory response. Fenofibrate, a third generation fibric acid derivative and peroxisome proliferator-activated receptor-α ligand, is involved in the regulation of inflammatory response. However, the participation of macrophages in this scenario has not been elucidated. Here we show, for the first time, that macrophages play a fundamental role in the fenofibrate-mediated modulation of heart pro-inflammatory response and fibrosis caused by the infection with Trypanosoma cruzi. Furthermore, macrophages are required for fenofibrate to improve the loss of ventricular function and this restoration correlates with an anti-inflammatory microenvironment. Understanding the contributions of macrophages to the healing properties of fenofibrate reinforces its potential use as a therapeutic drug, with the aim of helping to solve a public health problem, such as chronic Chagas disease.

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

“…We have previously demonstrated that fenofibrate is able to decrease tissue inflammation, ameliorate ventricular dysfunction, and prevent heart fibrosis in a chronic murine model of mixed T. cruzi infection. , Additionally, we highlighted the significant contribution of macrophages to these effects . Nevertheless, the effects of fenofibrate on both the early activation profile and function of cardiac macrophages, as well as on the acute inflammatory and fibrotic response of the heart, remains unexplored.…”

“…However, here, we demonstrate that early fenofibrate treatment altered neither the parasitemia nor heart parasite load. These results support earlier studies conducted by our group, not only in the case of fenofibrate, − but also in the case of HP 24 treatment …”

“…22,23 Additionally, we highlighted the significant contribution of macrophages to these effects. 24 Nevertheless, the effects of fenofibrate on both the early activation profile and function of cardiac macrophages, as well as on the acute inflammatory and fibrotic response of the heart, remains unexplored. Thus, we established an acute model of myocarditis using C57BL/6 mice, known for their heightened susceptibility to T. cruzi infection, 27 by infecting them with the pantropic-reticulotropic and highly virulent RA strain of T. cruzi.…”

“…cruzi infection. , Additionally, we recently demonstrated the crucial involvement of macrophages in the fenofibrate-induced modulation of the heart’s pro-inflammatory response and fibrosis resulting from T. cruzi infection …”

“…22,23 Additionally, we recently demonstrated the crucial involvement of macrophages in the fenofibrate-induced modulation of the heart's pro-inflammatory response and fibrosis resulting from T. cruzi infection. 24 Taking into account the aforementioned aspects, the aim of this research was to investigate how fenofibrate modulates both the phenotype and function of cardiac macrophages as well as its effect on the inflammatory and fibrotic response of the heart. Likewise, the study sought to analyze the effect of treatment on the ventricular function in the context of acute Chagas inflammatory myocarditis.…”