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+ LY6Chigh). Furthermore, both CD11b+ Ly6Clow F4/80high macrophages (MΦ) and recently differentiated CD11b+ Ly6Chigh F4/80high monocyte-derived macrophages (MdMΦ) shift toward a resolving phenotype (CD206high) 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.

Macrophages Mediate Healing Properties of Fenofibrate in Experimental Chagasic Cardiomyopathy.

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.

Hepatic injury associated with Trypanosoma cruzi infection is attenuated by treatment with 15-deoxy-Δ12,14 prostaglandin J2.

Trypanosoma cruzi, the etiological agent of Chagas' disease, causes an intense inflammatory response in several tissues, including the liver. Since this organ is central to metabolism, its infection may be reflected in the outcome of the disease. 15-deoxy-Δ12,14 prostaglandin J2 (15dPGJ2), a natural agonist of peroxisome-proliferator activated receptor (PPAR) γ, has been shown to exert anti-inflammatory effects in the heart upon T. cruzi infection. However, its role in the restoration of liver function and reduction of liver inflammation has not been studied yet. BALB/c mice were infected with T. cruzi. The effects of in vivo treatment with 15dPGJ2 on liver inflammation and fibrosis, as well as on the GOT/GPT ratio were studied and the role of NF-κB pathway on 15dPGJ2-mediated effects was analysed. 15dPGJ2 reduced liver inflammatory infiltrates, proinflammatory enzymes and cytokines expression, restored the De Ritis ratio values to normal, reduced the deposits of interstitial and perisinusoidal collagen, reduced the expression of the pro-fibrotic cytokines and inhibited the translocation of the p65 NF-κB subunit to the nucleus. Thus, we showed that 15dPGJ2 is able to significantly reduce the inflammatory response and fibrosis and reduced enzyme markers of liver damage in mice infected with T. cruzi.

Low-dose benznidazole treatment results in parasite clearance and attenuates heart inflammatory reaction in an experimental model of infection with a highly virulent Trypanosoma cruzi strain.

Chagas disease, caused by Trypanosoma cruzi, is the main cause of dilated cardiomyopathy in the Americas. Antiparasitic treatment mostly relies on benznidazole (Bzl) due to Nifurtimox shortage or unavailability. Both induce adverse drug effects (ADE) of varied severity in many patients, leading to treatment discontinuation or abandonment. Since dosage may influence ADE, we aimed to assess Bzl efficacy in terms of parasiticidal and anti-inflammatory activity, using doses lower than those previously reported. BALB/c mice infected with the T. cruzi RA strain were treated with different doses of Bzl. Parasitaemia, mortality and weight change were assessed. Parasite load, tissue infiltrates and inflammatory mediators were studied in the heart. Serum creatine kinase (CK) activity was determined as a marker of heart damage. The infection-independent anti-inflammatory properties of Bzl were studied in an in vitro model of LPS-treated cardiomyocyte culture. Treatment with 25 mg/kg/day Bzl turned negative the parasitological parameters, induced a significant decrease in IL-1ß, IL-6 and NOS2 in the heart and CK activity in serum, to normal levels. No mortality was observed in infected treated mice. Primary cultured cardiomyocytes treated with Bzl showed that inflammatory mediators were reduced via inhibition of the NF-κB pathway. A Bzl dose lower than that previously reported for treatment of experimental Chagas disease exerts adequate antiparasitic and anti-inflammatory effects leading to parasite clearance and tissue healing. This may be relevant to reassess the dose currently used for the treatment of human Chagas disease, aiming to minimize ADE.

Impaired Trypanosoma cruzi-specific IFN-gamma secretion by T cells bearing the BV9 T-cell receptor is associated with local IL-10 production in non-lymphoid tissues of chronically infected mice.

The role of non-lymphoid tissue T cells expressing the BV9 family T-cell receptor (TCRBV9) was studied in mice chronically infected with the Trypanosoma cruzi. Heart and skeletal muscles had higher frequencies and ratios of CD8+ TCRBV9+ to CD4+ TCRBV9+ T cells than lymph nodes. Also, homing experiments of CFSE-labeled T cells showed preferential homing of TCRBV9+ T cells to heart tissue. In vitro proliferation assays showed higher [3H]thymidine uptake by non-lymphoid tissue TCRBV9+ T cells than lymph node TCRBV9+ T cells co-cultured with antigen-presenting cells (APC), in response to T. cruzi amastigote antigens (TcAg). Lymph node TCRBV9+ T cells secreted IFN-gamma and IL-10, but not IL-4, upon stimulation with TcAg in the presence of APC. Moreover, non-lymphoid tissue-derived TCRBV9+ T cells showed impairment of IFN-gamma, no IL-4 production, and higher levels of IL-10 secretion under the same conditions. Our results show that T. cruzi-specific IFN-gamma- and IL-10-producing TCR BV9+ T cells develop in the mouse lymph nodes during chronic infection with T. cruzi. Upon homing to non-lymphoid parasitized tissues, IFN-gamma secretion might subside due to the overt secretion of IL-10, of which TCRBV9+ T cells represent a significant source.