Betulinic Acid Derivative BA5, Attenuates Inflammation and Fibrosis in Experimental Chronic Chagas Disease Cardiomyopathy by Inducing IL-10 and M2 Polarization.

Cássio Santana Meira,Juliana Fraga Vasconcelos,Iasmim Diniz Orge,José Maria Barbosa-Filho,Emanuelle De Souza Santos,Daniela Nascimento Silva,Alex Cleber Improta Caria,Breno Cardim Barreto,Renan Fernandes Do Espírito Santo,Milena Botelho Pereira Soares,Simone Garcia Macambira,Diogo Rodrigo Magalhães Moreira,Carolina Kymie Vasques Nonaka

doi:10.3389/fimmu.2019.01257

Abstract

Chronic Chagas disease cardiomyopathy (CCC) is a major cause of heart disease in Latin America and treatment for this condition is unsatisfactory. Here we investigated the effects of BA5, an amide semi-synthetic derivative betulinic acid, in a model of CCC. Mice chronically infected with T. cruzi were treated orally with BA5 (10 or 1 mg/Kg), three times per week, for 2 months. BA5 treatment decreased inflammation and fibrosis in heart sections but did not improve exercise capacity or ameliorate cardiac electric disturbances in infected mice. Serum concentrations of TNF-α, IFN-γ, and IL-1β, as well as cardiac gene expression of pro-inflammatory mediators, were reduced after BA5 treatment. In contrast, a significant increase in the anti-inflammatory cytokine IL-10 concentration was observed in BA5-treated mice in both tested doses compared to vehicle-treated mice. Moreover, polarization to anti-inflammatory/M2 macrophage phenotype was evidenced by a decrease in the expression of NOS2 and proinflammatory cytokines and the increase in M2 markers, such as Arg1 and CHI3 in mice treated with BA5. In conclusion, BA5 had a potent anti-inflammatory activity on a model of parasite-driven heart disease related to IL-10 production and a switch from M1 to M2 subset of macrophages.

Highlights

Chagas disease, caused by the flagellate protozoan Trypanosoma cruzi, affects 7 million people worldwide [1]
We found a potent immunomodulatory activity of BA5 in vitro, decreasing the production of crucial inflammatory mediators, including nitric oxide (NO), tumor necrosis factor alpha (TNF-α) and inhibiting the activation of nuclear factor-κB (NF-κB), a transcription factor that regulates the expression of several pro-inflammatory genes [14]
We evaluated the effects of BA5 administration in the cardiac tissue, by analyzing heart sections stained with hematoxylin and eosin and Sirius red for quantification of inflammation and fibrosis, respectively

Summary

Introduction

Chagas disease, caused by the flagellate protozoan Trypanosoma cruzi, affects 7 million people worldwide [1]. Endemic in Latin American countries, it is increasingly found in non-endemic countries due to intense flow of migration, representing a major public health problem [2]. The acute phase of Chagas disease is characterized by the presence of T. cruzi parasites in the bloodstream, which trigger an intense inflammatory response in several tissues, especially in the cardiac tissue [3, 4]. The majority of T. cruzi-infected patients survive in the acute phase and develop a chronic asymptomatic infection [5]. After a variable period of time (10–30 years after the onset infection), about 30% of chronically-infected patients become symptomatic [6].

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Conclusion