Enhanced Migratory Capacity of T Lymphocytes in Severe Chagasic Patients Is Correlated With VLA-4 and TNF-α Expression

Abstract

Trypanosoma cruzi infection in humans leads to progression to chronic chagasic myocarditis (CCM) in 30% of infected individuals, paralleling T cell inflammatory infiltrates in the heart tissue. T-cell trafficking into the hearts of CCM patients may be modulated by in situ expression of chemotactic or haptotactic molecules, as the chemokine CXCL12, the cytokine tumor necrosis factor-alpha (TNF-α), and extracellular matrix proteins (ECM), such as fibronectin. Herein we evaluated the expression of fibronectin, CXCL12, and TNF-α in the myocardial tissue of T. cruzi seropositive (asymptomatic or with CCM), as well as seronegative individuals as healthy controls. Hearts from CCM patients exhibited enhanced expression of these three molecules. CXCL12 and TNF-α serum levels were also increased in CCM individuals. We then evaluated T lymphocytes from chronic chagasic patients by cytofluorometry, in terms of membrane expression levels of molecules involved in cell activation and cell migration, respectively, HLA-DR and the VLA-4 (very late antigen-4, being one integrin-type fibronectin receptor). Indeed, the expression of HLA-DR and VLA-4 was enhanced on T lymphocytes from chagasic patients, especially in the CCM group. To further approach the dynamics of T cell migratory events, we performed fibronectin-, TNF-α-, and CXCL12-driven migration. Peripheral blood mononuclear cells (PBMCs) and T cells from CCM patients presented an ex vivo enhanced migratory capacity driven by fibronectin alone when this ECM protein was placed in the membrane of transwell migration chambers. When TNF-α was previously placed upon fibronectin, we observed a further and significant increase in the migratory response of both PBMCs and T lymphocytes. Overall, these data suggest the existence in patients with chronic Chagas disease of a cardiac inflammatory infiltrate vector that promotes the recruitment and accumulation of activated T cells, driven in part by enhanced tissue expression of fibronectin and TNF-α, as well as the respective corresponding VLA-4 and TNF receptors.

Genome-wide association study for Chagas Cardiomyopathy identify a new risk locus on chromosome 18 associated with an immune-related protein and transcriptional signature

“…In fact, monocytes, macrophages, and the plasma of patients with the indeterminate form produce significantly higher amounts of IL-10 compared to individuals with CCC [ 38 – 41 ]. In contrast, pro-inflammatory cytokines, such as gamma interferon (IFN-γ), TNF, and IL-17, are at higher levels in TCD4, TCD8, and monocyte cells, in addition to serum and plasma from patients with CCC [ 42 – 45 ]. This association has been also replicated at the transcriptional level [ 46 – 47 ].…”

Increased Trypanosoma cruzi Growth during Infection of Macrophages Cultured on Collagen I Matrix

“…To evaluate the cytokine production by macrophages, a control group of non-infected cells was introduced to compare the basal levels between infected groups and collagen I models. It is known that the proinflammatory cytokine TNF-α produced by macrophages is essential in the immune response against T. cruzi [40]. The cytokine analysis shows no difference in TNF-α production between macrophages cultured and infected on a 3D matrix, 2D biofilm, or directly on the polystyrene surface of the 24-well plate (Figure 5A).…”

Cytokine Networks as Targets for Preventing and Controlling Chagas Heart Disease

“…This scenario contributes to cardiomyocyte apoptosis and, consequently, to heart tissue damage and remodeling, which involves fibrosis [ 39 , 64 , 76 , 77 ]. In addition, these immune mediators may contribute to cellular recruitment and survival of inflammatory T cells in the myocardium [ 42 , 78 ].…”