Role of SOCS2 in Modulating Heart Damage and Function in a Murine Model of Acute Chagas Disease

Abstract

Infection with Trypanosoma cruzi induces inflammation, which limits parasite proliferation but may result in chagasic heart disease. Suppressor of cytokine signaling 2 (SOCS2) is a regulator of immune responses and may therefore participate in the pathogenesis of T. cruzi infection. SOCS2 is expressed during T. cruzi infection, and its expression is partially reduced in infected 5-lipoxygenase-deficient [knockout (KO)] mice. In SOCS2 KO mice, there was a reduction in both parasitemia and the expression of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), IL-6, IL-10, SOCS1, and SOCS3 in the spleen. Expression of IFN-γ, TNF-α, SOCS1, and SOCS3 was also reduced in the hearts of infected SOCS2 KO mice. There was an increase in the generation and expansion of T regulatory (Treg) cells and a decrease in the number of memory cells in T. cruzi-infected SOCS2 KO mice. Levels of lipoxinA(4) (LXA(4)) increased in these mice. Echocardiography studies demonstrated an impairment of cardiac function in T. cruzi-infected SOCS2 KO mice. There were also changes in calcium handling and in action potential waveforms, and reduced outward potassium currents in isolated cardiac myocytes. Our data suggest that reductions of inflammation and parasitemia in infected SOCS2-deficient mice may be secondary to the increases in Treg cells and LXA(4) levels. This occurs at the cost of greater infection-associated heart dysfunction, highlighting the relevance of balanced inflammatory and immune responses in preventing severe T. cruzi-induced disease.

Role of the Aryl Hydrocarbon Receptor in the Immune Response Profile and Development of Pathology during Plasmodium berghei Anka Infection

“…For example, the tryptophan photoproduct 6-formylindolo [3,2-b]carbazole and kynurenine, endogenous AhR ligands, increase only the Th17 population (37,40), while 2,3,7,8-tetrachlorodibenzo-p-dioxin, a high-affinity exogenous AhR ligand, appears to expand only the Treg cell population (preventing experimental autoimmune encephalomyelitis) (42). Additionally, we demonstrated that AhR expression is associated with modulation of the expression of SOCS, a well-known class of molecules contributing to the regulation of cytokine receptor signaling pathways important in the modulation of the immune response against infection (46,52). In this regard, SOCS1 and SOCS3 expression counteracts the actions of IFN-␥ and IL-6 (46,52,77), which play important roles in the pathogenesis of CM.…”

“…The suppressor of cytokine signaling (SOCS) family plays an important role in immune responses by modulating cytokine signaling pathways, and AhR has been shown to modulate SOCS2 expression in the mouse model of T. gondii infection (46). SOCS2 is also induced during T. cruzi infection (52) and was shown to be modulated as a result of aspirin treatment (53). Therefore, we examined SOCS1, -2, and -3 expression in the brain tissue of infected mice.…”

“…Additionally, we demonstrated that AhR expression is associated with modulation of the expression of SOCS, a well-known class of molecules contributing to the regulation of cytokine receptor signaling pathways important in the modulation of the immune response against infection (46,52). In this regard, SOCS1 and SOCS3 expression counteracts the actions of IFN-␥ and IL-6 (46,52,77), which play important roles in the pathogenesis of CM. Since there was a reduction in the expression of SOCS1 and SOCS3 in infected AhR-KO mice, one would expect that the inflammatory milieu found in the infected brain would have a greater ability to induce CM.…”

“…While Treg cells have been involved in the regulation of the immune response to malaria, the precise mechanism by which Treg cells modulate cerebral pathology is still unclear. In different models of infection, Treg cells have been described to be important in the modulation of T cell responses (52,54,72). During CM, Treg cells participate in the modulation of T cell recruitment to the brain.…”

Cardiomyocyte dysfunction during the chronic phase of Chagas disease

“…However, until now, few studies have provided compelling evidence of cardiomyocyte dysfunction during the establishment of heart failure following infection by T. cruzi (de Carvalho et al 1992, Pacioretty et al 1995, Roman-Campos et al 2009b. Recently, new data have provided supporting evidence of how the left ventricular electrical-mechanical dysfunction observed during the initial stages of chagasic cardiomyopathy occurs (Esper et al 2012, RomanCampos et al 2012. However, the cellular mechanisms underlying cardiomyocyte dysfunction during the late stages of Chagas disease remain unknown.…”