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Front. Immunol. | doi: 10.3389/fimmu.2019.01257

Betulinic acid derivative BA5, attenuates inflammation and fibrosis in experimental chronic Chagas disease cardiomyopathy by inducing IL-10 and M2 polarization

Cássio S. Meira1, Emanuelle S. Santos1, Renan F. Santo1, Juliana F. Vasconcelos1,  Iasmim D. Orge1,  Carolina K. Nonaka1,  Breno C. Barreto1, Alex C. Caria2, Daniela N. Silva1, Jose M. Filho3, Simone G. Mamcabira4,  Diogo R. Moreira1 and  Milena B. Soares1*
  • 1Gonçalo Moniz Institute (IGM), Brazil
  • 2Centro de Biotecnologia e Terapia Celular, Brazil
  • 3Federal University of Paraíba, Brazil
  • 4Federal University of Bahia, Brazil

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 two 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.

Keywords: Trypanosoma cruzi, Betulinic acid derivative, Immunomodulation, cardiomyopathy, Chagas Disease

Received: 14 Mar 2019; Accepted: 17 May 2019.

Edited by:

Christoph Hölscher, Forschungszentrum Borstel (LG), Germany

Reviewed by:

Thomas Jacobs, Bernhard-Nocht-Institut für Tropenmedizin (BMITM), Germany
Celio G. Freire-de-Lima, Federal University of Rio de Janeiro, Brazil  

Copyright: © 2019 Meira, Santos, Santo, Vasconcelos, Orge, Nonaka, Barreto, Caria, Silva, Filho, Mamcabira, Moreira and Soares. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Milena B. Soares, Gonçalo Moniz Institute (IGM), Salvador, Bahia, Brazil, milena@bahia.fiocruz.br