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However, an exacerbated respiratory burst from macrophages can damage tissues where parasites reside, such as the heart and liver. Subsequent fibrotic repair in the heart contributes to cardiomyopathy in patients with chronic Chagas disease and in mouse models. Additionally, respiratory burst metabolites are implicated in the impairment of CD8+ T cell responses. While excessive reactive oxygen species production is associated with increased differentiation of Foxp3+ regulatory T cells, T cell receptor nitration occurs in the presence of high extracellular nitric oxide (NO) levels. Both mechanisms contribute to CD8+ T cell suppression during T. cruzi infection. In this study, we use metformin (Metf) to balance parasite control and immune-mediated tissue damage by modulating macrophage activation. We found that Metf ex vivo treatment in peritoneal macrophages (PEMs) from acutely infected mice led to reduced inducible NO synthase expression, decreased NO production, and lowered secretion of interleukin-1\u03b2, tumor necrosis factor, and IL-6. However, IL-12 levels increased and CD8+ T cells cocultured with these PEMs showed enhanced proliferation and interferon \u03b3 production. In vivo, Metf-treated infected mice exhibited lower parasitemia and improved CD8+ T cell functionality, potentially linked to reduced T cell receptor nitration and decreased regulatory T cell frequencies in the peritoneum, as well as reduced cardiac inflammation. These findings provide new insights into the inflammatory modulation exerted by Metf and its potential impact on CD8+ T cell response and Chagas disease outcome.<\/jats:p>","DOI":"10.1093\/jleuko\/qiaf134","type":"journal-article","created":{"date-parts":[[2025,9,25]],"date-time":"2025-09-25T12:06:43Z","timestamp":1758802003000},"source":"Crossref","is-referenced-by-count":4,"title":["Metformin improves CD8+ T cell responses and parasitemia control via macrophage modulation during\n                    <i>Trypanosoma cruzi<\/i>\n                    infection."],"prefix":"10.1093","volume":"117","author":[{"given":"Ruth Eliana","family":"Baigorri","sequence":"first","affiliation":[{"name":"Centro de Investigaciones en Bioqu\u00edmica Cl\u00ednica e Inmunolog\u00eda, Consejo Nacional de Investigaciones Cient\u00edficas y T\u00e9cnicas, C\u00f3rdoba ,","place":["Argentina"]},{"name":"Departamento de Bioqu\u00edmica Cl\u00ednica, Facultad de Ciencias Qu\u00edmicas, Universidad Nacional de C\u00f3rdoba, Av. 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