Tolerogenic Dendritic Cells Reduce Cardiac Inflammation and Fibrosis in Chronic Chagas Disease.

Emanuelle De Souza Santos,Luciana Souza De Aragão-França,Cássio Santana Meira,Lain Carlos Pontes-De-Carvalho,Jéssica Vieira Cerqueira,Carolina Kymie Vasques Nonaka,Juliana Fraga Vasconcelos,Milena Botelho Pereira Soares

doi:10.3389/fimmu.2020.00488

Emanuelle De Souza Santos, Luciana Souza De Aragão-França + Show 6 more

Open Access

https://doi.org/10.3389/fimmu.2020.00488

Copy DOI

Abstract

Chronic Chagas disease cardiomyopathy (CCC) is the most frequent and severe form of this parasitic disease. CCC is caused by a progressive inflammation in the heart, resulting in alterations that can culminate in heart failure and death. The use of dendritic cells (DCs) appears as an option for the development of treatments due to their important role in regulating immune responses. Here, we investigated whether tolerogenic cells (tDCs) could interfere with the progression of CCC in an experimental model of Chagas disease. The tDCs were generated and characterized as CD11b+ CD11c+ cells, low expression of MHC-II, CD86, CD80, and CD40, and increased expression of PD-L. These cells produced low levels of IL-6 and IL-12p70 and higher levels of IL-10, compared to mature DCs (mDCs). Interestingly, tDCs inhibited lymphoproliferation and markedly increased the population of FoxP3+ Treg cells in vitro, compared to mature DCs. In a mouse model of CCC, treatment with tDCs reduced heart inflammation and fibrosis. Furthermore, tDCs treatment reduced the gene expression of pro-inflammatory cytokines (Ifng and Il12) and of genes related to cardiac remodeling (Col1a2 and Lgals3), while increasing the gene expression of IL-10. Finally, administration of tDCs, increased the percentage of Treg cells in the hearts and spleens of chagasic mice. Ours results show that tolerogenic dendritic cells have therapeutic potential on CCC, inhibiting disease progression.

Highlights

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi, and affects about 8 million people worldwide, mainly low income populations [1]
The analysis by flow cytometry of CD11b+ CD11c+ population showed a lower expression of CD40, CD80, CD86, and MHC-II in tolerogenic dendritic cells (tDCs) (Figures 1A–C)
The tDCs produced lower levels of IL-6 and IL-12, and higher levels of IL-10, compared to mature DCs (mDCs) (Figures 2A–C). These results indicate a regulatory phenotype of tDCs generated from bone marrow cells by treatment with dexametosone in vitro

Summary

Introduction

Chagas disease is caused by the protozoan parasite Trypanosoma cruzi, and affects about 8 million people worldwide, mainly low income populations [1]. The acute phase of Chagas disease is characterized by high parasitemia with immune-inflammatory response to the parasite, which result in organ damage [4]. Most of the patients remain asymptomatic without clinical manifestations. About 20–40% of the chronic patients, develop the cardiac and/or digestive forms of the disease, for which there are no available treatments [5, 6]. The chronic Chagas disease cardiomyopathy (CCC) is most frequent and severe manifestation found, with symptoms that range from mild to severe cardiac remodeling associated with

Objectives

Methods

Results

Conclusion