TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-α blockade

Abstract

In Chagas disease, understanding how the immune response controls parasite growth but also leads to heart damage may provide insight into the design of new therapeutic strategies. Tumor necrosis factor-alpha (TNF-α) is important for resistance to acute

Chronic Trypanosoma cruzi-elicited cardiomyopathy: from the discovery to the proposal of rational therapeutic interventions targeting cell adhesion molecules and chemokine receptors - how to make a dream come true

“…Increased CCR5 expression by CD8 + T cells was detected after in vitro stimulation with a T. cruzi antigen (Machado et al 2005), demonstrating the central role of the parasite in CCR5 modulation. We have also recently demonstrated that TNF signalling via TNFR1 is crucial for CD8 + CCR5 + differentiation, CD8 + CD44 + CD62L -/low compartmentalisation and CD8 + T cell-enriched myocarditis formation during T. cruzi infection (Kroll-Palhares et al 2008).…”

Interferon-γ and other inflammatory mediators in cardiomyocyte signaling during Chagas disease cardiomyopathy

“…In vitro experiments have shown that IFN-γ may induce profound changes in the cardiomyocyte gene expression program, including induction of atrial natriuretic factor and of the hypertrophic gene expression program, which can ultimately lead to heart dilation and heart failure [8] . Other inflammatory mediators and chemokines such as IL-18 and CCR7 ligands, upmation in response to chemokines such as CCL2, CCL3, CCL4, CCL5, CXCL10 and CCR5 [41] . The blockade of one, CCR5, by Met-RANTES significantly decreased the intensity of cardiac inflammatory infiltrate, suggesting that lymphocyte migration to the myocardium during acute infection is dependent on CCR5 ligands [42,43] .…”

Influence of environmental enrichment on the behavior and physiology of mice infected by Trypanosoma cruzi

“…The regulatory cytokine IL-10 acts mainly to control the parasite in the acute phase of infection, inhibiting the action of TNF, which intensifies the inflammatory process 55 . Thus, it is assumed that the presence of TNF at the beginning stage of infection is essential for controlling parasite infection, but its intensification and persistence during longer periods of infection would prejudice the host due to the intensification of the tecidual inflammatory response and consequent functional organ sequel 56 . By decreasing the TNF concentration, environmental enrichment enhanced the immune responses of the mice 56 .…”

“…Thus, it is assumed that the presence of TNF at the beginning stage of infection is essential for controlling parasite infection, but its intensification and persistence during longer periods of infection would prejudice the host due to the intensification of the tecidual inflammatory response and consequent functional organ sequel 56 . By decreasing the TNF concentration, environmental enrichment enhanced the immune responses of the mice 56 . The chemokine CCL2 promotes the attraction of inflammatory cells to inflammatory sites, and together with TNF, it is responsible for the myocarditis induced by parasitism 17 .…”