Differential Role of TGF-β in Extracellular Matrix Regulation During Trypanosoma cruzi-Host Cell Interaction.

Tatiana Araújo Silva,Luis Felipe De Carvalho Ferreira,Claudia Magalhães Calvet,Mirian Claudia De Souza Pereira

doi:10.3390/ijms20194836

Tatiana Araújo Silva, Luis Felipe De Carvalho Ferreira + Show 2 more

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https://doi.org/10.3390/ijms20194836

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Abstract

Transforming growth factor beta (TGF-β) is a determinant for inflammation and fibrosis in cardiac and skeletal muscle in Chagas disease. To determine its regulatory mechanisms, we investigated the response of Trypanosoma cruzi-infected cardiomyocytes (CM), cardiac fibroblasts (CF), and L6E9 skeletal myoblasts to TGF-β. Cultures of CM, CF, and L6E9 were infected with T. cruzi (Y strain) and treated with TGF-β (1–10 ng/mL, 1 h or 48 h). Fibronectin (FN) distribution was analyzed by immunofluorescence and Western blot (WB). Phosphorylated SMAD2 (PS2), phospho-p38 (p-p38), and phospho-c-Jun (p-c-Jun) signaling were evaluated by WB. CF and L6E9 showed an increase in FN from 1 ng/mL of TGF-β, while CM displayed FN modulation only after 10 ng/mL treatment. CF and L6E9 showed higher PS2 levels than CM, while p38 was less stimulated in CF than CM and L6E9. T. cruzi infection resulted in localized FN disorganization in CF and L6E9. T. cruzi induced an increase in FN in CF cultures, mainly in uninfected cells. Infected CF cultures treated with TGF-β showed a reduction in PS2 and an increase in p-p38 and p-c-Jun levels. Our data suggest that p38 and c-Jun pathways may be participating in the fibrosis regulatory process mediated by TGF-β after T. cruzi infection.

Highlights

Chagas disease (CD), caused by the flagellated protozoan Trypanosoma cruzi [1], currently affects 6–8 million people worldwide [2]
The main cell type responsible for ECM synthesis in the myocardium, are the effector cells in the cardiac fibrosis process, [37], and that cell lines originated from skeletal muscle respond to Transforming growth factor β (TGF-β) in picomolar concentrations [38], we evaluated the expression of extracellular matrix components in uninfected and T. cruzi-infected cardiac fibroblasts and skeletal muscle cells (L6E9) after treatment with different concentrations of TGF-β and analyzed the underlying signaling mechanisms of these processes
In an attempt to understand the mechanisms underlying cardiac fibrosis evidenced in the pathogenesis of Chagas disease, we evaluated the modulation of extracellular matrix components in cardiomyocytes (CM), cardiac fibroblasts (CFs), and L6E9 skeletal myoblasts stimulated with TGF-β, Int

Summary

Introduction

Chagas disease (CD), caused by the flagellated protozoan Trypanosoma cruzi [1], currently affects 6–8 million people worldwide [2]. The disease scenario has shifted to a global threat due to migration of infected individuals to non-endemic areas [3,4]. CD presents in acute and chronic clinical forms. While the former is typically inapparent or presents only mild manifestations and is commonly ignored due to non-specific signs, the latter, asymptomatic in approximately 70% of cases, may progress to severe damage. Chronic Chagas cardiomyopathy (CCC), estimated to be present in 20–30% of infected individuals [6,7], is the most severe manifestation in CD with a high morbidity and mortality and has significant economic and social impacts in Latin America [8]

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