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

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.

GWAS loci associated with Chagas cardiomyopathy influences DNA methylation levels

“…In addition, CCDC88B has been also described in a murine model as relevant in the immune function of dendritic cells [30]. In this sense, one subtype of dendritic cells, the tolerogenic dendritic cells, have been recently proposed to have therapeutic properties in a mouse model of chronic Chagas cardiomyopathy, given their role in the reduction of inflammation and fibrosis that contributes to reduce disease progression [35,36]. Interestingly, the CCDC88B was previously reported to suffer changes in its methylation and expression levels when cardiac tissues from patients with chronic Chagas cardiomyopathy and healthy donors were compared, showing also a correlation among both methylation an expression variations [16].…”

Regulatory T Cells in Chronic Heart Failure

“…Finally, they achieved a beneficial effect on ventricular remodeling (62). Similarly, the effects of tDCs in increasing the number of Tregs had also been reported in autoimmune myocarditis and chronic Chagas disease mice (63,64). DCs enhanced Treg functions in inhibiting the proliferation and accumulation of effector T cells likewise, which avoid excessive autoimmune response caused by cardiac injury (77).…”

“…④tDCs increased antigen-specific Tregs and produced beneficial effects in MI. In vitro, antigen-loaded DC or GM-GSF-stimulated DC induced the proliferation of Tregs (62)(63)(64). The number of DCs increased in the hearts in both acute injury and HF.…”

Reestablishment of Redox Homeostasis in the Nociceptive Primary Afferent as a Mechanism of Antinociception Promoted by Mesenchymal Stem/Stromal Cells in Oxaliplatin-Induced Chronic Peripheral Neuropathy

“…Four weeks after MSC transplantation, mice were euthanized and sciatic nerve samples (±1 cm) and DRG (L4-L5) were collected and processed for the gene expression analysis by real-time quantitative polymerase chain reaction (qRT-PCR). The transcription of the antioxidant genes superoxide dismutase ( Sod1 ) and nuclear factor-2 erythroid related factor-2 ( Nrf2 ) was evaluated as described by Santos et al [ 52 ]. RNA was extracted of the sciatic nerve and DRG samples using TRIzol reagent (Invitrogen Molecular Probes, Eugene, OR, USA), and the RNA concentration was determined by photometric measurement (NanoDrop 2000c Spectrophotometer; Thermo Fisher Scientific, Waltham, MA, USA).…”